ReviewArticle Is p53 Involved in Tissue-Specific Insulin...

Review ArticleIs p53 Involved in Tissue-Specific Insulin Resistance Formation

Justyna Strycharz1 Jozef Drzewoski2 Janusz Szemraj3 and Agnieszka Sliwinska4

1Diabetes Student Scientific Society at the Department of Internal Diseases Diabetology and Clinical PharmacologyMedical University of Lodz Lodz Poland2Department of Internal Diseases Diabetology and Clinical Pharmacology Medical University of Lodz Lodz Poland3Department of Medical Biochemistry Medical University of Lodz Lodz Poland4Department of Nucleic Acid Biochemistry Medical University of Lodz Lodz Poland

Correspondence should be addressed to Agnieszka Sliwinska agnieszkasliwinskaumedlodzpl

Received 16 September 2016 Accepted 19 December 2016 Published 17 January 2017

Academic Editor Miguel Constancia

Copyright copy 2017 Justyna Strycharz et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

p53 constitutes an extremely versatile molecule primarily involved in sensing the variety of cellular stresses Functional p53utilizes a plethora of mechanisms to protect cell from deleterious repercussions of genotoxic insults where senescence deservesspecial attention While the impressive amount of p53 roles has been perceived solely by the prism of antioncogenic effect itspresence seems to be vastly connected with metabolic abnormalities underlain by cellular aging obesity and inflammation p53has been found to regulate multiple biochemical processes such as glycolysis oxidative phosphorylation lipolysis lipogenesis 120573-oxidation gluconeogenesis and glycogen synthesis Notably p53-mediated metabolic effects are totally up to results of insulinaction Accumulating amount of data identifies p53 to be a factor activated upon hyperglycemia or excessive calorie intake thuscontributing to low-grade chronic inflammation and systemic insulin resistance Prominent signs of its actions have been observedin muscles liver pancreas and adipose tissue being associated with attenuation of insulin signalling p53 is of crucial importancefor the regulation of white and brown adipogenesis simultaneously being a repressor for preadipocyte differentiation This reviewprovides a profound insight into p53-dependent metabolic actions directed towards promotion of insulin resistance as well aspresenting experimental data regarding obesity-induced p53-mediated metabolic abnormalities

1 Introduction

Obesity is now referred to as a global pandemic and itsprevalence is expected to grow in enormously rapid way[1 2] Environmental factors such as high calorie intakeaccompanied by reduced energy expenditure are still per-ceived as its major drivers what explains profound epigeneticresearch [3] Nevertheless the genetic aspect of obesity hasnever been ignored [4ndash6] Obesity constitutes an excellentbackground for a plethora of life-threatening disorders suchas type 2 diabetes (T2D) cardiovascular diseases NAFLD(nonalcoholic fatty liver disease) and many cancers [7ndash10]Inevitably adiposity is tightly linked to metabolic syndrome(Mets) The latter one encompasses a group of metabolicallyrelated cardiovascular risk factors also known to augment theprogression of diabetes [11] The escalating global incidenceof T2D is alarming being enriched by the expectance of

diabetes to become 7th leading cause of death in 2030 [12]Due to such dramatic data there is a great need to investigatethe pathomechanism underlying diabetes which is alwaysaccompanied by numerous vascular complications [13] p53is an incredibly versatile molecule mainly involved in sensingcellular stresses thereby acting as a potent tumour suppressor[14] An accumulating amount of data suggests that p53 isinvolved in the pathomechanism of metabolic abnormalitiestriggered by obesity and hyperglycemia This review sum-marizes findings regarding p53 role in the phenomenon ofinsulin resistance

2 Insulin Signalling Pathway andInsulin Resistance

21 Insulin Signalling Insulin is an anabolic hormoneinvolved in the regulation of glucose and lipid homeostasis

HindawiOxidative Medicine and Cellular LongevityVolume 2017 Article ID 9270549 23 pageshttpsdoiorg10115520179270549

2 Oxidative Medicine and Cellular Longevity

IRSppp

ppp

p

pPI3K

PIP2PIP3

PDK1

GlycogenolysisLipolysis

ProteolysisGluconeogenesis

PTEN

LipogenesisGlycogenesis

Protein synthesis

Insulin

GLUT 4vesicle

Glucose

GLUT 4Insulin

receptor

Cell growthsurvival

ShcGrb2

Sos

MAPKcascade

Cell growth

AKT

pp

p

p ppp p

120577120582PKC 120577120582

120572120572

120573120573

Figure 1 Insulin signalling pathway Upon insulin stimulation activation of insulin receptor and thus formation of many phosphotyrosineresidues do occur Binding of IRS proteins and their phosphorylation precedes recruitment of PI3K as well as subsequent PIP2phosphorylation Note that PIP3 can be converted to PIP2 through PTEN activity PDK1 gets activated upon binding to PIP3 followedby the phosphorylation of PKC 120577120582 and AKT which stimulate GLUT4 translocation towards cell membrane and therefore glucose influxPhosphorylated AKT mediates the repression of glycogenolysis lipolysis proteolysis and gluconeogenesis as well as the activation oflipogenesis glycogenesis protein synthesis and cell survival The stimulation of insulin receptor is also accompanied by binding of adaptorproteins known as Shc The subsequent binding of Grb2 and Sos proteins initiates the MAPK cascade pathway The activation of AKT andMAPK cascade results in the promotion of cell growth

[15] Insulin receptor (IR) is a tyrosine kinase receptorwhich requires dimerization and binding of insulinmoleculesfor activation This heterotetrameric receptor is madeup of 2 extracellular 120572 subunits and 2 transmembrane120573 subunits Autophosphorylation of IR results in cre-ation of many phosphotyrosine residues which serve asdocking sites for subsequent components of this signallingpathway PTP-1B (protein-tyrosine phosphatase 1B) utilizesits phosphatase activity to reverse the process of recep-tor activation thus being one of several negative regula-tors of insulin signalling [16] Multiple phosphotyrosinesallow for recruitment and phosphorylation of various sub-strate proteins where IRS (insulin-receptor substrate) pro-teins deserve special attention [17] Phosphorylated IRSsactivate and direct PI3K (phosphatidylinositol-3-kinase)to plasma membrane PI3K phosphorylates PIP2 (phos-phatidylinositol 45-bisphosphate) thereby generating PIP3(phosphatidylinositol-345-trisphosphate) PIP3 is the keylipid signalling intermediate undergoing dephosphorylationby two lipid phosphatases SHIP2 (SH2-containing inosi-tol 51015840-phosphatase-2) and PTEN (phosphatase and tensinhomolog) [18] Increased level of PIP3 activates serine thre-onine kinase PDK1 (phosphoinositide-dependent proteinkinase-1) thus allowing phosphorylation and subsequent

activation of PKBAKT (protein kinase B also known asAKT) and atypical PKC 120577120582 (protein kinase C) [19 20]Both of them increase insulin-induced glucose uptake bytriggering translocation of GLUT4 (glucose transporter 4)from intracellular vesicles to cell membrane Not only is AKTan antiapoptotic molecule [21] but also its activity results inall metabolic effects mediated by insulin [22] AKT phos-phorylates numerous downstream targets thereby repressingglycogenolysis lipolysis proteolysis and gluconeogenesisOn the other hand AKT stimulates lipogenesis glycogenesisand protein synthesis Undoubtedly insulin is a potentgrowth factor triggering cell growth and differentiation [15]Its mitogenic activity is exerted mainly through stimulationofmitogen-activated protein kinase (MAPK) cascade Insulinsignalling pathway is depicted in Figure 1

22 Insulin Resistance Insulin action is indispensable for themaintenance of energy balance It affects a large number ofkinases and enzymes during fasting and feeding periods toenable proper functioning of the entire organism Insulinresistance is the condition characterized by lowered responseof cells to circulating insulin While the precise molecularmechanism remains to be elucidated insulin resistance isalways manifested by disturbances in insulin signalling thus

Oxidative Medicine and Cellular Longevity 3

leading to its attenuation There are several molecular path-ways which have been suggested to play a great role in thiscomplex metabolic disorder [23] As obesity is still the majorrisk factor the role of free fatty acids is of crucial importancePhysiologically insulin is secreted from 120573 cells upon raisedglucose level and acts on tissues enabling quick storage ofenergy surplus Therefore insulin signalling ultimately leadsto translocation of tissue-specific glucose transporters tocell membrane causing glucose influx When calorie intakeexceeds the demanded one energy is primarily deposited inwhite adipocytes which are the only cells for safe fat storage[24] If this state is prolonged hypertrophy and hyperplasiaof adipocytes set in Hence the induction of adipose tissuehypoxia leads to low grade chronic inflammation which trig-gers insulin resistance [25] As insulin cannot further storeenergy in adipocytes its raised amount is needed for com-pensation Consequently 120573 cells undergo adaptive changesin order to produce and secrete an incredibly large amountof insulinWhile insulin sensitivity is decreased its inhibitoryimpact on lipolysis is relievedThis results in increased level ofcirculating free fatty acids subsequently taken up by musclesliver and pancreas Thus all these tissues become affectedby lipotoxicity leading directly to the induction of nonadi-pose tissue insulin resistance Then gluconeogenesis andglycogenolysis are no longer suppressed triggering glucoseoutput from the liverMeanwhile inflammation in adipocytesexacerbates in parallel with their necrosis due to intensifiedmacrophages infiltration Hyperinsulinemia leads to 120573-cellsexhaustion which makes their function decline Thereforethe glucose intolerance along with hyperglycemia is estab-lished [26] 120573 cell mass reduction up to 60 precedes the firstclinical manifestations of type 2 diabetes [27] Clearly insulinresistance is closely associated with obesity and is underlainby oxidative stress along with inflammation [26]

3 p53 Overview

TP53 gene has been declared the major tumor suppressorgene [28] as the prevailing number of its actions are per-ceived by the prism of conferring protection to the genomeConsequently loss of wild type p53 is commonly linked to thephenomenon of tumorigenesis [29] making p53 reactivationamiraculous and promising target in anticancer therapy [30]This transcription factor is broadly known to be activated inthe presence of the plethora of genotoxic insults like hypoxiaoxidative stress DNA damage and oncogene activation tomention only the most important ones [14] Dependingon the stress severity and the extent of DNA damage p53decides whether to save the affected cell or perform thesuicidal death to protect it from changing its phenotype toa malignant one Activated p53 is forced to implementimmediate antiproliferative program yet this is accomplisheddue to a range of cellular events such as apoptosis senescence(irreversible cell growth arrest) or cell cycle arrest [14 31ndash33] Induction of cell cycle arrest gives p53 a possibility toperform DNA repair [34] underscoring the relevance ofp53 as a mediator of prosurvival and cytoprotective effectOn the other hand apoptosis and senescence are claimedto be leading ways of p53 tumor suppressive program as

they are realized when the stress causes irreparable andhighly hazardous DNA damage Regardless of the type ofimplemented actions p53 always aims to stop the propagationof deleterious mutations Nevertheless the exact molecularandmechanistic implications enabling p53 to choose betweenliving or dying still arouse some controversy [35]

TP53 gene product is a broadly known transcriptionalactivator without being a direct transcriptional repressor[36] Alternatively p53 can mediate transrepression by pre-venting the binding of other transcriptional activators to theirtarget sites [37] Its nontranscriptional activities involve directprotein-protein interactions with Bcl2 family of apoptosis-regulatory proteins [38 39] Thereby p53 induces mitochon-drial outer membrane permeabilization and cytochrome crelease finally triggering apoptosis

The major cellular gatekeeper [40] is entangled into thecomplex gene regulatory network composed of its mediatorseffectors and coregulators [41 42] Mediators are sensitizersof stresses determining p53 actions by marking it withadequate PTMs (posttranslational modifications) In thisreview ATM (ataxia teleangiectasia mutated) and AMPK(AMP-activated protein kinase) are of great importanceEffectors constitute a group of more than one hundred geneswhich exhibit p53-mediated specific cellular effects p21 isconsidered as a master p53 effector participating in thecell cycle arrest and senescence [43 44] Its expression level isundoubtedly an indicator of p53 tumour suppressor activityMoreover p53 is known to increase expression of proapototicgenes such as PUMA (p53-upregulated modulator of apop-tosis) [45] NOXA [46] and Bax [47] While coregulatorsclosely cooperate with p53 they trigger histonemodificationsas well as changes in chromatin structure [48] Consideringthe abundance of p53 target genes and functions the varietyof posttranslational modifications applied to this single pro-tein should not be surprising [49] Numerous PTMs influ-ence p53 stability and determine its subsequent actions inresponse to different stimuli enabling cellular lifeguard to actquickly and with extreme precision [50]

31 Regulation of p53 Activity The ldquoguardian of the genomerdquois subjected to sophisticated regulation [51] Namely itsstability and amount are precisely regulated by its closestnegative regulatorMDM2 (mouse doubleminute 2 homolog)[52 53] This E3 ubiquitin ligase forms a complex withp53 and determines its fate due to the attachment of ubiq-uitin molecules Highly expressed MDM2 conducts p53polyubiquitination thereby triggering its nuclear degrada-tion MDM2-dependent p53 monoubiquitination mediatesnuclear exclusion of p53 and precludes its transcriptionalactivity [54] Noticeably p53 ubiquitination level is highlydependent on the MDM2 activity [54] When the genotoxicstressor occurs MDM2 activity and p53 degradation arerepressed p53 undergoes the process of stabilization andaccumulation followed by tetramerization and binding totarget DNA sequences [55] As p53 induces expression of itsclosest negative regulator together they form autoregulatoryfeedback loop being relevant to the maintenance of balancedcellular conditions Physiologically p53 shuttles between two


Cellular growthand survival

Unstressed cell

Nuclear proteosomal degradation

Proteasomal degradation

Nucleus

pp

IRSpp

p p

PI3K

PIP2PIP3

PDK1

AKTThr 308 Ser 473

MDM2

p p

MDM2

pp

p53

MDM2

p p

p53

p53 RETarget genes

Ser 186 Ser 166

Ser 186 Ser 166

Ser 186 Ser 166

Figure 2The crosstalk betweenMDM2p53 and PI3KAKT pathways under physiological conditions Insulin signalling triggers the cellulargrowth and survival Activated AKT performs MDM2 Ser166 and 186 phosphorylation thereby allowing for degradation of p53 in thecytoplasm and nucleus Thus p53 cannot transcriptionally regulate the plethora of target genes where these enabling cell cycle arrestsenescence and apoptosis are of crucial importance Blue lines denote molecular mechanisms present under physiological conditions REstands for response element See text for more details

major cellular compartments cytoplasm and nucleus in acell-cycle dependent manner [56]

As previously mentioned AKT is subjected to phospho-rylation upon insulin stimulation [57] Ser473 and Thr308phosphorylations are demanded formaximal activity of AKT[57] This molecule has been reported to perform MDM2Ser166 and Ser186 phosphorylations [58] Hence MDM2entry into nucleus is promoted [59] and also its self-ubiquitination is limited [60] Moreover it decreases p53transcriptional activity and stimulates MDM2 ubiquitin lig-ase activity thereby leading to increased rate of p53 degrada-tion [61] (Figure 2) When the stressor occurs p53 aims toblock the cell growth and survival Thus it triggers AKTdegradation and transactivates PTEN a prominent PIP3phosphatase (Figure 3) Notably PTEN was demonstrated tophysically interact with p53 and promote its acetyla-tion tetramerization DNA binding and transcriptionalactivity by utilizing phosphate-dependent and phosphate-independent mechanisms [62 63] Moreover PTEN-p53interaction was potent enough to reverse MDM2-mediatedinhibition of p53 [64] Another research team showed thatoroxylin-induced PTEN is capable of reducing the rate ofMDM2 transcription and thus favours p53 stabilization [65]

In the case of stressor occurrence ATM kinase undergoesSer1981 phosphorylation thereby being released from theinhibitory self-dimer complex [66 67] Concomitantly itinfluences p53 stability by phosphorylating Ser15 (Ser18 inmice) [68 69] In order to preclude p53 degradation ATMconducts MDM2 Ser395 phosphorylation [70] InterestinglyATM was also shown to inhibit MDM2 by affecting its RINGdomain oligomerization as well as its E3 ligase processivity[71] In general ATM activation releases MDM2-mediatedinhibitory mechanism thereby allowing p53 stability (Fig-ure 3) ATM further potentiates p53 activity level by revolvingaround the suppression of an impressive amount of p53inhibitors [72] Prominently p53 gets immediately deubiq-uitinylated thanks to USP10 (Ubiquitin Specific Peptidase10) activity [73] Moreover ATM activity elicits cascades ofmolecular events going hand in hand with the promotion ofefficient p53 translation level [72] It is promoted through thebinding of MDM2 to p53mRNA as well as by circumventingthe MDM2-mediated RPL26 (ribosomal protein L26) degra-dation [73 74] Interestingly MDM2-p53mRNA interactionis indispensable for p53 activation triggered upon DNAdamage therefore providing a deeper rationale for the p53-mediated MDM2 induction [75]This regulatory mechanism


Translationalmachinery

RPL26

Nucleus

USP10

Stressoroccurrence

p53

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AKT

p53

p

p

p53 RE

PTENp53 p53

p53 p53p p

p pATMSer 1981

MDM2

p

Ser 395p

PTEN

PTEN

p53 mRNA

p53 mRNA

MDM2

MDM2

p

p

Ser 395

Ser 395

PIP3 PIP2

PDK1

ppIRS

ppPI3K

PTEN

pSer 15

Ser 15

Stressor

Figure 3The crosstalk between ATMMDM2p53 and PTENPI3KAKT pathways under the exposure to genotoxic and metabolic stressorATMkinase undergoes activation upon genotoxic stressor occurrence It conductsMDM2 Ser395 phosphorylation as well as phosphorylatingp53 at Ser15 MDM2 cannot negatively regulate p53 which immediately gets stabilized and accumulates Positive regulation of p53 isperformed due to its deubiquitination by activated USP10 Nuclear p53 tetramerization allows for transcriptional regulation of genes involvedin provision of antioncogenic cellular protection PTEN is one of the p53 target genes responsible for the inhibition of insulin signalling Inaddition to the blockage of phospho-AKT formation p53 triggersAKTproteosomal degradation p53 translation is enhanced by the formationof p53mRNA-MDM2 complex and inhibited RPL26 degradation While blue lines depict phenomena present upon stressor occurrence redlines represent inhibited signalling events RE stands for response element Only limited number of regulatory events is shown

adds a new dose of complexity to p53-MDM2 interactionsand sheds a new light on the tumour suppressive role ofMDM2

32 p53 Functions p53 roles are abundant and extremelydiverse (Figure 4) [76] Different cellular localization andconcentration might be factors determining p53 function[77] p53 is implicated among others in the antioxidantdefense [78] suppression and promotion of cellular differ-entiation [79 80] as well as aging [81]

Interestingly p53 has been declared a ldquoguardian of differ-entiationrdquo due to its prominent impact on several mesenchy-mal differentiation programs [79] Interestingly p53 plays adual role in terms of adipogenesis [80] While it is positivelyinvolved in brown adipogenesis it suppresseswhite adipocytedifferentiation [80]

p53 plays a dual role with respect to oxidative stress phe-nomenon [77] Excessive ROS (reactive oxygen species) accu-mulation induces genomic instability being a trigger for p53activation Consistently p53 transactivates genes associated

Cell cyclecontrol

Antioxidantdefense

p53

DNA repair Aging

White andbrown

adipogenesis

Metabolism

Apoptosis Senescence

Figure 4 Cellular phenomena vastly influenced by p53

with antioxidant defense such as SESN1 and SESN2 (sestrin 1and 2 resp) which reduce the level of ROS and protect cellsfrom the deleterious effects of oxidative stress Antioxidantgenes are subjected to permanent activation as lack offunctional p53 results in increased ROS level followed by


Oxidativephosphorylation

Lypolysis120573-oxidation

Glucose influxGlycolysis

LipogensisGlycogenesis

Gluconeogenesis

p53 Insulin

Figure 5 Opposed metabolic regulation executed by p53 and insulin

DNA damage [78] This sequence of events was confirmedin numerous normal and carcinoma cell lines indicating thefundamental way in which p53 exerts its antioncogenic effect[78] On the other hand induction of prooxidant genes isa mechanism used by p53 to induce apoptosis in a ROS-dependent manner [77 82] As chronic inflammation under-lies the process of tumorigenesis it is another stimulus forp53 activation [83 84] p53 is entangled in a broad crosstalkwith inflammatory elements such as previously mentionedROS cytokines or NF120581B (nuclear factor kappa-light-chain-enhancer of activated B cells) [84] Although NF120581B-p53relationship abounds in a variety of mechanisms enablingtheir mutual repression [85] p53 was suggested to elicitinflammation through the activation of NF120581B pathway [86]Surprisingly NF120581B might be an indispensable molecule forp53-dependent induction of apoptosis [87]

Moreover mild oxidative stress condition intensifies theintroduction of single-stranded damages into telomere struc-tures [88] Damage and shortening of telomeres form generaltelomere dysfunctionality which provokes p53 activation andresults in either senescence or apoptosis [89 90] Neverthe-less senescence is considered as a major mechanism pro-tecting the cells from the effects mediated by this genotoxicstressor [91] Shortened telomeres are a vivid sign of cellularaging simultaneously creating a link with p53 signallingHowever the exact p53 role in aging is still inconclusive andhighly debatable as studies suggest that p53 can function asboth its enhancer or repressor [81]

p53 is capable of responding to metabolic stresses Forinstance glucose deprivation state is sensed through AMPK(51015840AMP-activated protein kinase) which activates p53 andelicits its transcriptional program [92] Metabolic stressorswhich constitute a great threat towards replication fidelityforce p53 to shut down mitogenic signalling expressed by theinhibition of IGF-1AKT and mTOR (mammalian target ofrapamycin kinase) pathways [93] Depending on the stressortype p53 was proved to regulate the expression of TSC2(tuberin) IGF-BP3 (insulin-like growth factor-binding pro-tein 3) and PTEN as well as AMPK [94] All these moleculesnegatively affect both the previously mentioned mitogenicpathways in a tissue or cell type specific way Notably thestimulation of PTEN and TSC2 expression was especiallyshown in all insulin-responsive tissues

As newmolecules associatedwith p53 still enter the arenathe intricate nature of the whole regulatory network advances

in a very rapid way Consistently numerous profound studiesstill indicate new plausible roles of the guardian of thegenome surpassing expectations of even the most staunchp53 researchers [95]

4 p53-Orchestrated Regulation of Metabolism

The versatility of p53 has also dominated metabolism whichgives a new dimension to its antioncogenic actions Utilizingtranscriptional activation as well as other mechanisms pro-tein 53 has a great impact on glycolysis oxidative phospho-rylation nucleotide biosynthesis and autophagy as well asglutaminolysis or fatty acid oxidation [96] All in all p53 hasemerged as an essential regulator of metabolic homeostasis[96]This statement becomes especially prominent in the caseof the Warburg effect which is a pivotal mark of cancer cellsIt is manifested by predominant dependence on glycolyticpathway for ATP synthesis simultaneously neglecting oxida-tive phosphorylation Wild type p53 has a vastly opposingrole expressed by inhibition of glycolysis and promotionof oxidative phosphorylation As vividly seen metabolic-oriented actions of p53 are directed towards neutralizationof the Warburg effect and the restoration of physiologicalway of ATP production Nevertheless the increased risk ofcarcinogenesis in patients suffering from obesity and diabetesgives some clues about a possible link to p53 function[97] The effects of p53 actions are totally opposed to theeffects mediated by insulin (Figure 5) therefore p53 canbe perceived as the molecule engaged in creating insulinresistance state [98] Below examples of p53-orchestratedmetabolic regulation are presented

41 p53-Dependent Regulation of Glucose Influx Glycolysisand Glycogenesis First p53 leads to decreased glucose influxby directly repressing expression of two glucose transportersGLUT1 and GLUT4 [99] The latter one might also berepressed through indirect mechanism [100] Namelyp53 was reported to downregulate PGC-1120572 (peroxisomeproliferator-activated receptor gamma coactivator 1120572) beingengaged in the stimulation of GLUT4 expression in muscletissue [100 101] Moreover p53 indirectly represses GLUT3expression by influencing other transcription factor NF120581B[102] The detailed mechanism is focused on the suppressionof IKK120572 and IKK120573 kinase activities being vital componentsof NF120581B signalling cascade


Additionally p53 affects the first component of insulinsignalling Namely insulin receptor (IR) promoter has beenshown to undergo repression mediated by p53 and accompa-nied by two other factors CEBP (CCAAT-enhancer bindingproteins) and Sp1 (specificity protein 1) [103]

p53-stimulated repression of glycolysis is executed inseveral ways First it performs inhibition of hexokinases HK1and HK2 and phosphoglycerate mutase (PGAM) which cat-alyze the first and eighth glycolysis steps [104 105] The latterone is not subjected to p53 transcriptional repression yetits protein stability is restricted [105] Hexokinasesrsquo upregu-lation is one of the most significant signs of cancerous phe-notype [106] simultaneously being the most crucial enzymefor glucose metabolism p53 represses hexokinases andphosphoglycerate mutase by inducing the expression ofmiR-34a [104] Nevertheless these enzymes can be likewisesubjected to opposite regulation thus creating evidence forp53-stimulated positive regulation of glycolysis [107 108]Theabove aspect highlights the relevance and complexity ofp53 actions Importantly p53-miR34 signalling pathway alsocontributes to the repression of GPI (glucose-6-phosphateisomerase) which catalyzes the second glycolytic reactionMoreover p53 overexpression itself has been reported tocorrelate with the decrease of another glycolytic enzymealdolase C (ALDC) [104]

TIGAR (TP53-induced glycolysis and apoptosis regula-tor) is a downstream p53 effector which acts as a suppressorof phosphofructokinase 1 (PFK) enzyme [109] PFK catalyzesthe third step of glycolytic pathway simultaneously beingthe rate limiting enzyme undergoing allosteric regulationby fructose-26-bisphosphatase TIGAR acts as fructose-26-bisphosphatase which causes the accumulation of fructose-6-phosphate followed by its isomerization to glucose-6-phosphate Not only is TIGAR claimed to be a glycolysisinhibitor but also the pentose phosphate pathway (PPP)enhancer is Additionally it provides protection against ROS-dependent damage by the production of NADPH needed forthe formation of reduced glutathione [109] TIGAR has beenshown to activate HK2 activity which can be perceivedas plausible mechanism enabling complex direction of gly-colytic intermediates to the pentose phosphate pathway thuscausing even more profound repression of aerobic glucoseoxidation [110]

RRAD (Ras-related associated with diabetes) wasrevealed to be overexpressed in some T2D diabetic patients[111] Furthermore it is likewise responsible for the reductionof glucose uptake in response to insulin stimulation inmuscle and adipose tissue [112] Recently it was found tobe a p53 target gene engaged in the repression of glycolysisunder hypoxic conditions [113 114] The exact mechanism iscentered on preventing the translocation of GLUT1 to thecellular plasma membrane Although the study was con-ducted on lung cancer tissue RRAD might be also subjectedto p53 regulation in insulin-responsive tissues

p53 was connected with restrained rate of glycogen syn-thesis in insulin-resistant subjects [115] Study data providedby Fang et al indicated that p63 which is a member of p53family is directly targeted by mir-20a-5p Reduced amountof this miRNA led to increased expression of p63 followed

by its physical interaction with p53 thus leading to increaseof p53 and PTEN Restriction of glycogenesis was proved tobe conducted through PTEN-mediated AKTGSK pathwayinhibition

42 p53-Mediated Enhancement ofOxidative PhosphorylationAltogether p53 is perceived as a negative glycolysis regulatordue to direct as well indirect repression of essential glycolyticenzymes P53 also performs glycolytic pathway limitationby profoundly promoting oxidative phosphorylation forATP synthesis The stimulation of glutaminolysis and fattyacid oxidation (FAO) as well as direct induction of genesinfluencingmitochondrial respiratory chain complexes vastlyameliorates this metabolic switch Furthermore such kindof metabolic control stays in agreement with p53 tumoursuppressive responsibility and presents totally opposite effectin comparison to insulin signalling (Figure 5)

In physiological conditions pyruvate an end productof glycolysis is converted to acetyl-CoA The latter oneserves as the entry molecule in tricarboxylic acid cycle(TCA) p53 increases the rate of acetyl-CoA formation due todirect regulation of genes affecting pyruvate dehydrogenase(PDH) the first enzymatic component of pyruvate dehy-drogenase complex P53 decreases the expression of PDK1and PDK2 (pyruvate dehydrogenase kinase 1 and pyruvatedehydrogenase kinase 2 resp) known to conduct repressivephosphorylation of PDH [104 116] In contrast p53 wasshown to increase the expression of PARK2 (parkin) whichpositively regulates PDH activity as well as strengtheningcellular antioxidant defense [117] Moreover p53-mediatedrepression of lactate dehydrogenase A (LDHA) protectspyruvate from conversion to lactate thus further promotingthe formation of acetyl-CoA [104]

p53 affects tricarboxylic acid cycle by directly inducingthe expression ofmitochondrial GLS2 (glutaminase 2) whichis commonly known to conduct the process of glutaminehydrolysis This results in the formation of glutamate andconsequent increase in the 120572-ketoglutarate level a compo-nent of TCA Consequently p53 intensifies mitochondrialrespiration and subsequent ATP production rate [118]

Direct p53 impact on oxidative phosphorylation is exe-cuted through the enhancement of SCO2 (synthesis ofcytochrome c oxidase) expression level The latter one reg-ulates COX (cytochrome c oxidase) complex a pivotal com-ponent of oxygen utilization [119] AIF (apoptosis-inducingfactor) is amitochondrial flavoprotein presumed to positivelyaffect the mitochondrial respiratory complex I Crucially p53performs constitutive activation of AIF expression therebyallowing efficient oxidative phosphorylation [120 121]

43 Impact of p53 on the Regulation of Gluconeogenesis Asinsulin exerts a repressive effect on gluconeogenesis it isworth to establish the accurate p53 role in gluconeogenicregulation Firstly the liver p53 level seems to be dynamicallyregulated by nutrient availability where activation of p53 andits target genes occurs in the case of food withdrawal throughthe AMPK-mediated mechanism [122] Another point isthat p53 was implicated to be a central node governing the


regulation of fasting in critical metabolic tissues such as livermuscles and adipose tissue [123] Interestingly the absenceof functional hepatic p53 results in defective gluconeoge-nesis thus promoting hypoglycemia [122] However studydata implicates both p53-induced suppressive [124 125] andstimulating [126ndash128] impact towards de novo glucose pro-duction The most recent findings suggest that p53 conductsdirect activation of sirtuin 6 (SIRT6) which in turn facilitatesexport of FoxO1 (forkhead box protein O1) to cytoplasm[124] Consequently FoxO1 is not capable of enhancingthe expression of two vast gluconeogenic executors PCK1(phosphoenolpyruvate carboxykinase 1) and G6PC (glucose6-phosphatase) Nevertheless the accumulating amount ofcontradictory data reflects the need for further confirmationof the exact p53 role in the regulation of this particularmetabolic pathway

44 Implications of p53 in the General Glucose HomeostasisAs seen above a large body of evidence indicates the vitalinfluence of p53 on glucose metabolism Besides biochem-ical implications p53 signalling seems to underlie generalphysiological glucose homeostasis [129 130] Its impact hasbeen observed in patients with A-T (ataxia teleangiectasia)which are highly susceptible to insulin resistance statefollowed by the development of T2D [131] ATM protein isthe trigger for A-T disease simultaneously being consideredas a molecular target in metabolic associated disorders [132133] It also acts as an upstream mediator of p53 function[134] As ATM kinase performs p53 activation through Ser18phosphorylation the mice model with p53S18A was usedto check the influence of ATM-p53 signalling pathway onthe physiological regulation of insulin sensitivity [129] Thismolecular defect turned out to be responsible for metabolicstress accompanied by glucose intolerance and subsequentinsulin resistance Insulin signalling was markedly reducedand associated with increased ROS level as this metabolicimbalance was reversed by the antioxidant treatment [129]Additionally it was revealed that a higher dose of p53 transac-tivation domain contributes to intensified protection againstany disturbances concerning glucose homeostasis [130] Inthis study the specific mice model with p53Ser18 defect wasutilized enabling observation of effects associated with theloss of p53-dependent activation of hzf (hematopoietic zincfinger protein) in white adipose tissue [135] Notably hzf isa vast adipogenesis regulator Mice exhibited adipose tissuespecific insulin resistance as well as increased level of TNF-120572along with notable decrease in adiponectin level The aboveresults confirm the significance of ATM-p53 signalling inmaintenance of glucose homeostasis Additionally it excep-tionally underscores the value of adipose tissue functionalitywhich if disturbed leads directly to insulin resistance andinflammation

On the other hand p53 knockoutmice did not exhibit anydifferences in insulin glucose and pyruvate tolerance testsin comparison to wild type mice [136] Insulin-stimulatedglucose uptake was not changed in adipocytes with siRNA-suppressed p53 expression Totally different findings origi-nated from studies performed on identically treated hepato-cytes Although glucose uptake turned out to be diminished

there were no changes in the expression of GLUT1 andGLUT2 in comparison to control hepatocytes Similarly thelevel of phosphorylated AKT was found to be equal in bothtypes of cells remaining exact p53-mediated mechanism tobe elucidated Nevertheless p53 itself was not indispens-able for general maintenance of glucose homeostasis [136]Intriguingly the lowered serum level of TP53 gene productwas reported in diabetic subjects as well as patients withimpaired glucose tolerance [137]

45 p53-Induced Regulation of Fatty Acid Metabolism p53has been observed to play a great role in both lipid catabolismand fatty acid 120573-oxidation [138] It contributes to the firstmetabolic pathway by directly stimulatingmolecules engagedin the release of fatty acids from lipids Namely it activatesproteins such as cytochromes P450-4F2 and 4F3 carnitineO-octanoyltransferase (CROT) and 2 types of carnitinepalmityltransferase CPT1A and CPT1C [138ndash141] Carnitineacetyltransferases are responsible for conjugating fatty acidsto carnitine which enables their transport to the mitochon-drial matrix [141] Cytochromes P450-4F subject long fattychain acids to hydroxylation leading to its 120573-oxidation [139]

Starvation-induced lipolysis was reported to be governedby p53 through stimulation of its downstream target Ddit4(DNA Damage Inducible Transcript 4) in adipocytes [123]The relationship between p53 and lipolysis was likewiseassociated with the chronic pressure overload and DNAdamage response in obese adipocytes [142 143]

Considering p53-mediated fatty acid oxidation regula-tion it must be stressed that all of them undergo activa-tion in the glucose deprivation state LPIN1 (lipin 1) andGAMT (guanidinoacetate N-methyltransferase) expressionlevels are subjected to p53-dependent increase [144 145]LPIN1 exhibits cooperation with two transcriptional reg-ulators PPAR120572 (peroxisome proliferator-activated receptoralpha) as well as PGC-1120572 [146]Their combined cellular effectis associated with the inhibition of the fatty acid synthesis andenhancement of fatty acid oxidation As mentioned beforep53 has been revealed to directly repress and interact withPGC-1120572 one of the master metabolic gene expression coacti-vators [101] Additionally PGC-1120572 constitutes a p53 regulatorforcing it to elicit transcriptional activation of genes involvedin the metabolic regulation and cell cycle arrest [147] GAMTexpression induction results in a vast increase of FAO rateby the mechanism involving stimulation of creatine synthesis[145]

PANK1 (pantothenate kinase-1) influences the level ofintracellular CoA (coenzyme A) by catalyzing the rate limit-ing step in CoA synthesis pathway [126] It has been reportedto be a direct positively regulated p53 transcriptional targetgene Mice lacking functional PANK1 gene and subjected tostarvation demonstrated defective120573-oxidation and gluconeo-genesis Therefore p53 was implicated to be an enhancer ofboth of these processes

Intriguingly FAO induction is also mediated by RP-MDM2-p53 metabolic response pathway RP (ribosomalprotein) becomes activated upon suppression of ribosomalbiogenesis occurring during metabolic stress As RP binds


MDM2 it contributes to subsequent p53 induction [148]Finally MCD (malonyl-coenzymeA decarboxylase) enzymecritically involved in the process of FAO undergoes p53-dependent upregulation RP-MDM2-p53 signalling pathwayhas a promoting impact on the mitochondrial fatty aciduptake as MCD enzyme regulates malonyl-CoA turnoverand subsequent CPT1120572 activation

Actions of the master tumour suppressor are also direct-ed towards inhibition of lipid anabolism Namely G6PD(glucose-6-phosphate dehydrogenase) is markedly represseduponp53 stimulation what leads to lowered efficiency of pen-tose phosphate pathway (PPP) and consequently to reducedNADPH level These events create a cellular signal whichdecreases lipogenesis [149]

SREBP1c (sterol regulatory element-binding protein 1c)which belongs to the family of transcription factors regulatingadipogenesis and lipogenesis [150 151] is subjected to p53-dependent downregulation [152] SREBP1c stimulates theexpression of FASN (fatty acid synthase) as well as ACLY(ATP citrate lyase) which were likewise revealed to undergop53-mediated repression [138 152]

Besides direct regulation of metabolic enzymes hypotha-lamic SIRT1p53 pathway was implicated in the responsetowards ghrelin the hormone regulating food intake [153]However mice lacking functional p53 were not characterizedby the impaired ghrelin-dependent stimulation of growthhormone secretion Moreover p53-mediated regulation ofadipogenic and lipogenic geneswas found to be indispensablefor ghrelin-induced storage of lipids in adipose tissue andliver [154]

5 Tissue-Specific p53-MediatedChanges Triggered by Obesityand Diabetic Conditions

Another piece of evidence linking p53 with glucose metab-olism is associated with its response towards glucose oscil-lations as well as hyperglycemic stimuli It has been estab-lished that hyperglycemia activates p53 and its downstreammediators in myocyte cells leading to its apoptosis [155]Additionally many studies have proved p53 activation uponhigh-fat and high-calorie diet treatment Discovery of thenew triggers for p53 induction encouraged the scientificcommunity to investigate p53 role in multiple tissues

51 p53 Role in the Pancreas The relationship betweenp53-dependent apoptosis hyperglycemia and mitochondrialdysfunction was widely investigated in pancreatic RINm5Fcells [156ndash158] First it is clear that hyperglycemia causesoxidative stress contributing to pancreatic 120573-cells apoptosis[159] The suggested mechanism is thought to be based onmitochondrial p53mobilization leading further to decreasedmitochondrial membrane potential followed by cytochromec release and fragmentation of nuclear DNA [156] Anotherstudy implied the plausible link between p53 Ser392 phos-phorylation and p38 MAPK activation in hyperglycemia-stimulated 120573-cells mass decrease [157 160] Inhibition of p38

MAPK activity coincided with the blockage of p53 translo-cation and decreased rate of apoptosis In other words p53ser392 phosphorylation was proved to be stimulated uponhyperglycemia and favor p53 mitochondrial translocation Inthe last similar study the MDM2-p53 regulatory status aswell ATM and AKT regulation was examined [158] AKTwas found to undergo hyperglycemia-dependent phospho-rylation and phosphorylated MDM2 at Ser166 [57 59ndash61158] Nevertheless MDM2 mRNA expression and proteinconcentration were vastly decreased High glucose seemed tosupport the formation of MDM2-p53 inhibitory complex inthe cytosol without any influence on its nuclear formationATM nuclear phosphorylation was reported to coincidewith p53 Ser15 phosphorylation indicating p53 activation[68 69] Despite the formation of MDM2-p53 complex p53was stabilized and its ubiquitination rate was limited In arecent review the authors suggest many plausible mecha-nisms adversely affecting MDM2-p53 autoinhibitory feed-back loop [161] It seems that MDM2 undergoes activationupon high glucose stimulus but its ubiquitin ligase activity isdisturbed This might happen due to hyperglycemia-inducedoxidative stress and consequent multiple phosphorylationevents Special emphasis is placed on the role of ATMkinase which could impair MDM2 ubiquitin ligase activityby the phosphorylation of some residues in RING-fingerand acid central domains Moreover p53 polyubiquitinationcan be reduced due to ROS-dependent limitation of cellularATP level According to the authors hyperglycemia sup-ports the formation of p53 PTMs such as phosphorylationpoly ADP-ribosylation and O-N-acetylglucosaminylationwhich probably contribute to its stabilization and subsequenttranslocation to mitochondria [162] All these findings areschematically depicted in Figure 6120573 cells apoptosis was found to be associated with AGE-

RAGEpathway [163]Not only canAGEs (advanced glycationend products) originate from food but they can also beformed in the process of nonenzymatic glycation of proteinsRAGE (receptor for advanced glycation end products) is areceptor known to bind glycated proteins An elevated level ofAGEs is one of themost vivid signs of chronic hyperglycemiasupporting pathogenesis of diabetic complications [164] p53was also found critical for apoptosis of 120573 cells in a glycation-serum-inducedmechanism [165] Studies performed on INS-1 cells and primary rat islets indicated that transcriptionalactivity of p53 becomes substantially increased in the pres-ence of glycation serum (GS) and contributes to cell apop-tosis Intriguingly 120573 cells demise was avoided upon p53inhibition which underlined the relationship between majortumour suppressor and AGE-RAGE pathway

In a study investigatingmitochondrial functionality alongwith GSIS (glucose induced insulin secretion) MDM2 andp53 expression levels in 120573-cells originating from diabeticmodels were found vastly upregulated [166] Lack of p53inhibition provoked repression of pyruvate carboxylase (PC)being mitochondrial enzyme engaged in the production ofoxaloacetate and NADPH Downregulation of these TCAcycle intermediates set the scene for the impaired oxygenconsumption ultimately leading to dysfunctional mitochon-drial metabolism and defective GSIS Given the obtained


Hyperglycemia

ATM activation

p53 stability

p53-MDM2complex withoutp53 degradation

MDM2 phosphorylation

and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation

Mitochondrial p53mobilization

Cytochrome C release

120573 cell mass decrease

Multiple kinasecascade activation

Reduced level ofATP

Oxidative stress

Decreased mitochondrialmembrane potential

Figure 6 Hyperglycemia-induced changes leading to p53-mediated 120573-cell mass decrease Red lines and arrows denote plausible mechanismsallowing p53 to avoid degradation in spite of p53-MDM2 complex formation

results the conjuncture of differential p53 role depending onthe stage of type 2 diabetes was made While slight increasein p53 level could repress GSIS the progression of diabetescould further stimulate p53 upregulation and evoke 120573-cellapoptosis thereby causing hyperglycaemia

Moreover glucolipotoxicity was shown to be a con-tributor to increased level of cytoplasmic p53 due to bothoxidative and ER stress [167] The suppressive interactionbetween p53 and Parkin was revealed to be a culprit forimpaired mitophagy in concert with disturbance of electronsystem transport and consequent cellular ATP deficit Thissequence of events eventually resulted in glucose intoleranceand impaired insulin secretion in animal models of bothtypes of diabetesWhileMDM2-p53 relationship still appearsintriguing another ubiquitin ligase ARF-BP1 was reportedto be critical for p53 activity in the context of age-relatedpancreatic120573-cells viability andhomeostasis In support of thisstatement activated p53 was proved to elicit acute diabeticsymptoms concurrently with rendering life span of arf-bp1mutant mice shorter [168]

According to Tavana et al NHEJ-p53R172Pmutantmicewhich demonstrated a combination of deficient p53 and non-homologous end-joining (NHEJ) exhibited severe diabetesand consequential death in early age [169] Accumulation ofDNA damage induced the increase of p53 and p21 which ledto cellular senescence along with the reduction of 120573 cell pro-liferation and overall depletion of pancreatic isletmass Otherstudies suggested that independently of the stimulus causing120573-cell metabolic stress the formation of DNA double strandbreaks along with consequent p53 induction constitutes themain mechanism leading to 120573-cells apoptosis [170] Revolv-ing around mechanistic details of p53 abundance mir-200dosage was delineated as a p53-amplifying factor promotingislets apoptosis in diabeticmice [171] Another study providedan insight into the role ofΔ40p53 the 44 kD p53 isoformwithtruncated transactivation domain in the context of 120573-cellsbiology [172] Δ40p53 is engaged in setting the balance

between all p53 isoforms Its overexpression endows cellswith highly stabilised p53 thereby instigating acceleratedaging attenuated cell proliferation as well as promotingsome abnormalities in terms of insulinIGF-1 signalling [172]Although Δ40 isoform of p53 has no transcriptional activityit does impact full-length p53 activity due to its ability to formtetramers Study results proved that Δ40p53 affected 120573-cellproliferation leading further to 120573-cells mass decrease Glu-cose intolerance along with hypoinsulinemia was establishedin 3-month old mice but the effect was progressing withage ultimately leading to overt diabetes and death Increasedlevel of p21 gene expression was also revealed Intrigu-ingly in another study stress-activated p21 was proved toevoke 120573-cell mass decrease through stimulation of intrinsicapoptotic pathway [173] By contrast p21 overexpressionwas found to be critical for 120573-cell recovery through thesuppression of 120573-cell duplication rate after streptozotocintreatment [174] Consistently deficiency or genetic ablation ofp21 deepened the effect of glucotoxicity on 120573-cells apoptosissimultaneously promoting diet-induced diabetes [175] Theuse of nutlin-3a the inhibitor of the interaction between p53andMDM2 stimulated p21 expression thus preventing fromthe ER-stress-mediated effects of prodiabetic conditions andprotecting 120573 cells from apoptosis Similarly nutlin-3 as anactivator of p53 was indicated to ameliorate streptozotocin-induced DM and proposed to provide antidiabetic effects[176] consequently raising some questions about the role ofp53MDM2 relationship

Moreover p53 was found to be entangled in the causalrelationship between 120573 cells demise and lipotoxicity throughFFA-dependent reduced activation of AKT and simultaneousincrease in p53 level [177] Chronic FFAs exposure was shownto stimulate p53 and consequential transcriptional activationof mir-34a in 120573-cells what elucidated alternative mechanismof 120573-cells apoptosis [178] In another study stearic acidcontributed to the activation of PERK (of protein kinase-like endoplasmic reticulum kinase) which stimulated p53


for induction of mir-34a-5p in islets of diabetic mice and invitro studies [179] Finally lipotoxicity was evoked throughconsequential reduction of BCL-2 (B cell CLLlymphoma 2)and BCL-W (BCL-2-like 2) direct targets of mir-34a-5p Itresulted in not only the potentiation of the susceptibility of120573 cells to apoptosis but also in the impairment of insulinsecretion

TCF7L2 (T-cell factor 7-like 2) is a transcription factorwhich has attracted a great deal of interest recently due toits causative impact on 120573-cells pathophysiology as well as itsassociation with type 2 diabetes [180] Its contributiontowards disturbed insulin secretion incretin effect andconsequential lowered 120573-cells survival was enriched by themolecular link with major tumor suppressor gene NamelyTCF7L2 was identified to employ p53-p53INP1 molecularpathway to negatively modulate the fate of islet 120573-cells [180]

Although the link between type 1 diabetes and p53 isbeyond the scope of this review potentiated activity of p53was likewise unequivocally demonstrated in the context ofthis type of 120573-cell dysfunction [181] The whole mechanismwas underlain by the presence of ROS and inflammatorycytokines which induced the activation of JNK and SAPKGAD65 (glutamic acid decarboxylase 65KDa isoform)which is a remarkably significant autoantigen underpinningpathomechanism of diabetes type 1 was reported to besubject to p53 regulation [182]

52 p53 Role in the Endothelium and Muscle Tissue Takinginto account the consequences of diabetes and obesity therole of endothelial dysfunction should not remain under-valued High-glucose incubation of endothelial cells evokedthe reduction of SIRT1 in concert with higher acetylationand activation of p53 which provoked the senescence anddysfunction of endothelial cells [183] The same results wereobtained in vivo [184] Endothelial ldquometabolic memoryrdquoformation in the presence of high glucose oscillations isalso being connected with p53 Here the crucial role forp53-MDM2 inhibitory feedback loop as well as prolongedactivation of its target genes after stressor removal is specif-ically underlined [185] Mitochondrial localization of p53is supposed to underlie metabolic memory phenomenonleading further to organelle dysfunction and oxidative stressaccompanied by mtDNA damage [155] Additionally p53rsquosremarkably negative impact has been noticed in endothelialprogenitor cells (EPC) [186] Both EPC cultured in dia-betic milieu and EPC from diabetic donors exhibited accel-erated senescence-like changes This effect coexisted withthe activation of AKTp53p21 signalling pathway pointingout the major role of p53 in the impairment of diabeticneovascularization On the other hand diet-induced obe-sity mice model enabled demonstration of endothelial p53as a vast inactivator of endothelial nitric oxide synthase(eNOS) [187] Further studies showed an increase in p53-dependent PTEN transactivation consequently affectingAkt-eNOSpathway Subsequently it decreased the expressionof PGC-1120572 in skeletal muscle followed by markedly reducedlevel of mitochondrial biogenesis and energy consumptionAdditionally deletion of endothelial p53 was manifested by

increased muscle glucose uptake due to lack of p53-GLUT1inhibitory regulation The upregulation of endothelial p53was claimed to be a causative agent of all observed metabolicabnormalities including intensification of insulin resistanceas well as fat accumulation Promisingly exercise supporteddownregulation of p53 and TIGAR in skeletal muscle ofGoto-Kakizaki (GK) rats without changes in SCO2 expres-sion [188] Therefore exercise implementation constitutesa weapon against the hazardous activity of p53 leading tolowered level of oxidative stress along with enhanced level ofmitochondrial DNA content

53 p53 Role in the Formation of Insulin Resistance in theLiver NAFLD (nonalcoholic fatty liver disease) is the generalterm defining liver abnormalities such as hepatic steatosisand nonalcoholic steatohepatitis (NASH) which can leadto fibrosis cirrhosis and hepatocellular carcinoma [189]NAFLD is associated with insulin resistance due to hepatictriglyceride accumulation connected with raised level ofcirculating free fatty acids Both of these factors furtherexacerbate the inflammation state ultimately forming avicious cycle [190] Upregulated p53 was confirmed to inducecytotoxicity exacerbating liver injury in various mice modelsof NAFLD [191] Another study investigated the impact ofp53 on apoptosis which is a basic mechanism favouringhepatocytes elimination in NAFLD [192] The amount of p53was dependent on the severity of liver steatosis and thuslinked to inflammation While p53 upregulation was parallelwith downregulation of antiapoptotic Bcl-2 proapoptoticBax expression was not changed Experimental murineNASH model exhibited p53 activation along with changes ofits downstream effectors [193] The induction of p21 sup-pression of antiapoptotic Bcl-XL and formation of t-Bidconfirmed the p53 role in the stimulation of intrinsic andextrinsic mitochondrial apoptosis pathways The same nutri-tional NASH mice model revealed that the induction ofp53 enhances p66Shc signalling ROS accumulation andhepatocyte apoptosis thereby promoting the progression ofsteatohepatitis [194] The expression changes obtained inthis mice model were confirmed by evaluation of liversamples from patients characterised by different severityof NAFLD Other findings connected NAFLD pathologywith p53miRNA34a pathway known to repress SIRT1 (sir-tuin1) expression [195] Selective p53 transcriptional activ-ity inhibitor called pifithrin-120572 (PFT) was administered tohigh-fat diet-induced NAFLD mice model As the p53-mediated inhibitory impact was relieved the activationof SIRT1PGC1120572PPAR120572 and SIRT1LKB1AMPK pathwayswas performed Consequently malonyl-CoA decarboxylase(MLYCD) underwent activation leading to the reduction ofmalonyl-CoA concentration As mentioned above this stepis always followed by the enhancement of CPT1 activitythereby inducing 120573-oxidation of fatty acids Notably thelevel of hepatic fat accumulation was diminished whichwas manifested by the lessening of steatosis oxidative stressand apoptosis Intriguingly PFT served as a factor loweringoverall fat accumulation upon high-fat diet treatment [195]Increased level of p53 in hepatic cells was reported in a


Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid

Intrinsicand extrinsic

mitochondrialapoptosispathway

Hepatocyteapoptosis

ROS

MLYCD and CPT1 inactivation

SIRT1PGC1120572PPAR120572

miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53

Figure 7 p53-induced cellular events promoting hepatocyte apoptosis

streptozotocin-induced animal model of diabetes [196] Allof the above mentioned p53-based mechanisms leading tohepatocytesrsquo apoptosis in the context ofNAFLD are presentedin Figure 7

p53 level was upregulated by the treatment of hepatocyteswith saturated fatty acids (SFA) along with its inhibitionresulting in the prevention of SFA-induced cell death [197]Once again the antagonism between p53 and insulin activ-ities was strongly highlighted as insulin treatment antago-nized the deleterious effects of p53 Moreover as mentionedabove p53 overexpression in livers of diabetic or NAFLDpatients could be caused by the downregulation of mir-20a-5p consequent suppression of glycogen synthesis and theintroduction of hepatic insulin resistance [115]

The previously observed connection between hepaticfibrosis and p53 accumulation in patients was investigatedon among others hepatocyte-specificMdm2-knockoutmice[198] Relief from MDM2 suppression prompted p53 to elicitspontaneous hepatic fibrosis This liver dysfunction did notoccur when p53 was subjected to concomitant deletionp53 indirectly promoted the synthesis of CTGF (connectivetissue growth factor) which is a molecule notorious for itsrelevant participation in fibrosis pathophysiology via down-regulation of miR-17-92 cluster gene [198]

Surprisingly the effect of p53 activity measured in thecontext of glucose homeostasis in insulin-resistant diabeticmice turned out to be highly beneficial and described asinsulin-like antidiabetic effect [199] Overexpressed p53improved plethora of biochemical indicators such as levelsof glucose or serum triglycerides Furthermore glycogenesisgenes were subjected to substantial upregulation concomi-tantly with downregulation of gluconeogenesis-associatedones Positive changes in hepatic and pancreatic gene expres-sion levels were reported for insulin receptor precursorPPAR-120574 GLUT2 and GK (glycerol kinase) All in all theseresults are in strong opposition to previous findings thusdemonstrating miraculous p53-stimulated effect on glucosehomeostasis with special focus on the amelioration of hepaticinsulin sensitivity

54 p53 Role in the Formation of Insulin Resistance in AdiposeTissue The very first implication for p53 elevation in classicinsulin-responsive tissues was shown in adipocytes of geneti-cally obese (119900119887119900119887) mice [152] The study aimed at evaluating

expression of p53 and its target genes (p21MDM2-2 Bax andIGFBP-3) during fasting and refeeding periods Surprisinglythe expression of all enumerated molecules was proved to beincreased upon refeeding stimuli In this study SREBP-1c wasrevealed to be downregulated by p53 highlighting the roleof p53 as an essential lipogenesis repressor The substantiallyelevated level of p53 was vividly linked with obesity-inducedinsulin resistance creating growing number of questionsassociatedwith the exact nature of its adipose tissue existence

The groundbreaking study conducted by Minamino et alestablished outstandingly important role of adipose tissue p53upregulation in augmenting insulin resistance [127] Most ofall white adipose tissue originating fromhigh-fat-diet treatedAy mice model exhibited p53 and p21 expression increaseThis observation suggested the induction of senescence-likephenotype Moreover the excessive levels of TNF-120572 (tumournecrosis factor) and CCL2 (chemokine C-C motif ligand 2)were found to occur due to senescence of both macrophagesand adipocytes The comparison of the results obtained fromtwo mice strains Ay Trp53+minus and Ay Trp53++ providedultimate evidence for p53 as a factor strongly exacerbatinginsulin resistance and glucose intolerance as well as inducingincreased insulin plasma level Additionally it has establishedp53 role in enhancing expression of hepatic gluconeogenicenzymes p53 was likewise indicated to participate in theformation of telomere-dependent insulin resistance Onthe other hand adipo-p53-deficient mice exhibited properinsulin signalling due to restoration of insulin-dependentAKT phosphorylation Results demonstrated that presenceof ROS leads to p53 activation followed by NF120581B-dependentinduction of proinflammatory cytokines Finally studies con-ducted on human adipose tissue removed during abdominalsurgery from diabetic and nondiabetic patients confirmedthe increased level of p53 protein and CDKN1A mRNAexpression Significantly inflammatory cytokines were ele-vated in adipose tissue originating from diabetic patientsAll of the above results point to a complex p53 role inthe pathophysiology of insulin resistance connecting it withinflammation telomere shortening and senescence of adi-pose tissue In this study the prominent role of cellular agingis highlighted shedding a new light on age-related obesityand insulin resistance Further studies conducted by thisresearch group found the evidence suggesting that Sema3E(semaphorin 3E) and its receptor plexinD1 may play a role in


Obesity

Semaphorin-plexinD

Macrophagesinfiltration

Senescent adipocytesand macrophages

ROS

Adipose tissueinflammation

Disturbed insulinsignalling

Insulin resistance

p53

Fat accumulation

Decreased insulinsensitivity

Proinflammatorycytokines

p21NF120581B

Figure 8 Obesity-induced p53-dependent molecular mechanisms occurring in adipose tissue and leading to insulin resistance

creating adipose tissue inflammation upon p53 activation inDIO (diet induced obesity) mice model [200] Sema3E is asecreted protein simultaneously transcriptionally activatedby p53 It was revealed to act as a chemoattractant therebydirectly triggering visceral fat inflammation along with allmetabolic abnormalities exacerbating insulin resistance stateThus Sema3E is suggested to be another potential therapeutictarget in the fight against insulin resistance Findings orig-inating from these highly relevant studies are visualized inFigure 8

An intriguing relationship between p53 and hyper-glycemia was observed in studies investigating the influ-ence of AGEs on senescent preadipocytes [201] RAGE-AGE axis was demonstrated to restore adipogenic functionof senescent preadipocytes whose adipogenic potential hadbeen repressed by age-related p53 activity Glycated proteinsstimulated RAGE to suppress p53 expression and modify itsfunctionality due to direct protein-protein interactions Alto-gether it seems that p53-stimulated preadipocyte senescenceis a mechanism providing protection against excessive age-related adiposity which might be reversed by AGE-RAGEaxis

Aside from hyperglycemia stimulus hyperinsulinemiawas also recognized as a factor strongly potentiating p53activity [202] The study conducted on 3T3-L1 adipocytesproved that increased p53 expression in concert withdecreased level of phospho-MDM2 disturbed insulin signal-ling and glucose uptake thus promoting hyperinsulinemia-induced insulin resistance Prominently p53 was subjected totime-dependent enhancement without signs of cytotoxicity

Adipose tissue p53 elevation has been reported to asso-ciate with chronic pressure overload [142] The exact path-omechanism was mediated by sympathetic nervous stimula-tion subsequently resulting in lipolysis promotion Notably

increased level of free fatty acids triggered adipocytic p53overexpression and promoted upregulation of proinflamma-tory cytokines in the NF120581B-dependent manner All of theabovementioned events elicited adipose tissue inflammationfollowed by insulin resistance and successive hyperinsu-linemia Ultimately p53 accumulation led to heart failuresimultaneously formingmetabolic vicious cycleThe detailedmechanism of p53-induced inflammation upon pressureoverload concerning endothelial and bone morrow cells hasbeen elucidated confirming its role in cardiac dysfunction[203] Diabetic cardiomyopathy was also demonstrated to beunderlain by diabetes-induced ROS-mediated increased lev-els of p53 and SCO2 Changes in gene expression extensivelystimulated mitochondrial oxygen consumption for unduegeneration of ROS thereby supporting lipid accumulationand cardiac dysfunction [204] Cardiomyopathy of diabeticsubjects was accompanied by raised levels of p53 and p21and decreased levels of mir-181a and mir-30c which werevalidated to directly target p53 [205]

The results provided by Vergoni et al strongly suggestedthat ROS-induced DNA oxidation occurring in the earlyonset of obesity was a rationale for p53 activation in obeseadipocytes [143] Studies conducted on 3T3-L1 cells as well asmice models implied that raised levels of p53 and p21 weresimply a response to DNA damage These molecular shiftswere followed by a classic cascade of events leading toinsulin resistance such as adipose tissue inflammationincreased macrophagesrsquo chemotaxis impaired insulin down-stream signalling along with insulin-induced glucose uptakeand increased lipolysis in affected adipocytes Conceivablyadipocytes were not found apoptotic due to the protectiveeffect of raised p21

Bogazzi and colleagues who examined male C57BL6Jtimes CBA mice proved that adipose p53 and growth hormone


(GH) pathways are converged which evoked the insulin-resistant phenotype upon high-fat diet treatment [206]Blockage of GH through p38 MAPK pathway was potentenough for normalization of p53 level in adipose depotssuggesting that GH action is indispensable for p53-triggeredmetabolic repercussions

In contrast a study conducted by Ortega et al pro-vided totally unexpected and contradictory results [207]The study was focused on the evaluation of adipose tis-sue p53 expression depending on the inflammation andinsulin resistance Impressively the results were obtainedfrom subjects characterized by a distinct degree of obesityand severity of insulin resistance as well as for several invivo and in vitro models The authors postulated that theupregulation of p53 is solely associatedwith factors triggeringinflammation such as senescence-connected shortening oftelomeres or progressive obesity Surprisingly the expressionof adipose tissue p53 was inversely correlated with insulinresistance and hyperglycemia The special attention was alsofocused on the level of p53 during adipogenesis which wasfound increasingly repressed Herein the causal connec-tion between inflammation and p53 expression was onceagain underlined as mature adipocytes produce a significantamount of anti-inflammatory adipokines High glucose levelwas another factor which intensified p53 downregulation inpreadipocytes Taken together p53 was subjected to dualand opposed regulation While inflammation stimulated itsexpression insulin resistance and high glucose neutralizedthis effect

p53 was found to be a repressor of preadipocyte differ-entiation [208] Although its expression was shown to beelevated at the beginning of the process it was then system-atically down-regulated [207 208] Importantly p53minusminus MEFcells were shown to exhibit lowered insulin-stimulated levelof phosphorylated AKT [208] Another results indicateddecreased level of adipogenesis marker genes due to over-expression of p53 [208] Opposed p53-mediated regulationof white and brown adipogenesis was also revealed [80]Moreover p53 knockout mice treated with high-fat high-sucrose (HFHS) diet exhibited a higher level of fat accu-mulation in comparison to their wild type counterpartsThese results imply that p53 provides protective effect againstdiet-induced obesity On the other hand p53 was shown tobe an indispensable component for proper formation andfunction of brown adipose tissue (BAT) [80] In a recentstudy p53 was revealed to influence brown adipose tissue viaconcurrent regulation of body weight and thermogenesis inthe diet-induced obesemice [209] It should be noted that p53was subjected to different types of repression performed ondifferent developmental stages and therefore itsmanipulationyielded different study results For example while micelacking p53 gene did not develop diet-induced obesity dueto previously mentioned mechanisms acute BAT-specificrepression of p53 in adult mice resulted in slight weight gainInterestingly pharmacologically activated p53 amelioratedbody weight by positively influencing thermogenesis in obeseadult p53-wild typemicemodel Notably brown fat is of greatrelevance to energy homeostasis being involved in energy

expenditure [210 211] While its reduced amount correlateswith insulin resistance [212] it is also established as a highlydetermining factor for metabolic syndrome in mice [213]In the light of emerging evidence enhancement of brownfat accumulation constitutes a novel and exciting approachin the battle against obesity [214] Summing up p53 canbe perceived as a miraculous molecule allowing protectionfrom obesity through confining white fat deposits as wellas supporting brown fat formation and functionality Dataobtained by Nakatsuka et al provide further confirmationfor this statement by elucidation of the exact mechanismexerted byRXR (retinoidX receptor) antagonistHX531 [215]Its antiobesity effect was accomplished through stimulationof p53p21 signalling pathway and related to suppresseddifferentiation of visceral adipocytes Furthermore G0G1cell cycle arrest was induced in mature adipocytes whichvastly reduced their hypertrophy On the contrary adiposetissue expansion has been attributed to p21 actions exhibitedupon HFHS diet [216] Not only was p21 presumed to havea stimulatory effect towards adipocyte differentiation butit was also implicated in the promotion of adipose tissuehyperplasia by protecting it from apoptosis Taken togetherp21 was prominently entangled in the creation of obesity andinsulin resistance upon high-fat diet treatment [216]

55 p53 Role in the Formation of Insulin Resistance in Insulinand Noninsulin Target Tissues Homayounfar et al evaluatedthe outcomes of p53 accumulation occurring in peripheraltissues of rats subjected to high fat diet (HFD) [217] Sur-prisingly p53 was found elevated in classic insulin targettissues (adipose muscle and liver) and in others (kidney andsmall intestine) Treatment with pifithrin-120572 (PFT) led todecreased amount of p53 in all examined tissues and provedthe crucial role of crosstalk between ATMMDM2p53 andPTENPi3KAKT pathways p53-mediated PTEN overex-pression was implicated to have a causative impact on theimpairment of insulin action Finally systemic application ofPFT repressed p53 action simultaneously improving insulinsensitivity reducing serum glucose level and enhancinginsulin cellular signalling In the most recent study obesity-induced p53-mediated deleterious metabolic effects wereinhibited by two agonists of 120573-adrenergic receptor in allinsulin target tissues [218] Both of themwere shown to stim-ulate elevation and activation of AKT along with a decreaseof p53 and phospho-p53 levels p53 inhibition was alsorevealed in noninsulin target tissues In other words agonistsof 120573-adrenergic receptor cannot be considered as insulinsensitizers as the risk associated with the lessening of p53-dependent antioncogenic cellular protection is too high

56 p53 and Age-Related Insulin Resistance While diabetesis widely known to accelerate the process of aging thereverse is likewise trueThe connection between p53 and age-associated insulin resistance seems to associate with cellularsenescence Above issue was firstly raised by Minamino et al[127] who indicated the causal relationship among obesityROS andDNAdamage generation shortage of telomeres andp53 activation This sequence of events consequentially led


to the introduction of senescent-like changes in adiposedepots thus stimulating an aging-associated insulin resis-tanceThe samewas implied in oxidative stress-exposed agingadipocytes [219] An aging-replicating mice model charac-terized by DNA repair impairment and DNA damage accu-mulation indicated the formation of p53-associated cellularsenescence in concert with a decline of pancreatic isletmass and the acquirement of severe diabetic phenotype[169] Moreover a deletion of ARF-BP1 phosphatase wasconcurrentwith activation of p53 in120573-cells which underwentan age-dependent depletion [168] Upregulation of p53 inthe liver muscle and adipose tissue was shown for olderand obese wild-type mice in comparison to control ones[220] Interestingly age-related p53 increase was preventedin PTP1Bminusminus mice which were proved to be insensitive todiet-induced changes of insulin sensitivity and characterizedby lean phenotype According to Jeon et al MCHminusminus miceexhibited resistance towards aging-induced accumulation ofbody mass as well as insulin resistance [221] In contrast toprevious studies p53 level decreased in response to aging inspleen and liver of MCHminusminus and wild-type mice in compari-son to their younger controls however the magnitude of p53decrease was lower in MCHminusminus ones

6 p53 Polymorphisms inDiabetes and Complications

Besides expression-based findings the connection betweendiabetes and p53 does have a genetic underlying Namelythe SNP occurring at p53 codon 72 is constantly examinedin the context of susceptibility to diabetes While subjectswith C nucleotide possess proline variant of p53 (R72) thesecarrying G allele have an arginine one (P72) Genetic studiesrevealed p53 codon 72 (Arg72Pro) polymorphism as a predis-posing factor for T2D in Finish Chinese Han and Europeanpopulations [222ndash224] which highlighted the independenceof this variant in the race-specific context The severity ofinsulin resistance observed in type 2 diabetic patients wasdemonstrated to associate with this polymorphism [225]Arg72Pro was also connected with waist circumference anddetermined the association betweenT2D andBMI [226 227]In the most recent study the above mentioned SNP wasexamined in the mice model and proved to increase therisk of obesity and general metabolic disturbances associatedwith insulin resistance and T2D [228] Moreover carriers ofrisk G allele demonstrated accelerated progression of diabeticnephropathy [229] Correlation between Arg72Pro polymor-phism and the early age of onset (lt6 years) was also found inItalian female T1D patients as well as being associated withthe development of polyneuropathy in Russian population[230 231] p53 polymorphism originating from 10 intronA17708Twas reported to coincidewith uremic complicationsin T2D subjects [232] Interestingly association between p53and diabetes-related complications was shown for diabeticcardiomyopathy [203ndash205] retinopathy [233] neuropathy[234] nephropathy [235] vasculopathy [183] peripheralarterial disease (PAD) [236] defective wound healing [237

238] testicular dysfunction [239 240] thrombocytic com-plications [241] or augmented apoptosis-based responsetowards ischemia [242] Worthily to note polymorphisms ofthe previously mentioned p53 transcriptional targets TCFL2(rs7903146) and p53INP1 (rs896854) were indicated tounderlie the risk for diabetes occurrence [243 244]

7 Conclusions

All of the above findings provide a profound insight intop53 actions trigged by adiposity or expressed upon diabeticconditions As can be seen some experimental results areinconsistent predominantly in adipose tissue It is likewiseassociated with p53 role in glucose homeostasis highlight-ing both its neutral and highly determining character Itsimpressive impact has been shown in other classic insulin-responsive tissues Clearly p53 is responsible for the forma-tion of tissue-specific insulin resistance aswell as being entan-gled into phenomenon of endothelial ldquometabolic memoryrdquoand many diabetic complications In the majority of studiesp53 was found to be elevated upon increased level of freefatty acids as well as high glucose stimulus As both triggerslead to diet-induced obesity activation of p53 affects numer-ous cellular phenomena especially shown in the form ofadipose tissue inflammation Herein it is impossible toundervalue the link between p53 and NF120581B whose recip-rocal interactions were earlier claimed to be predominantlyunderlain by functional antagonism The precise nature oftheir relationship seems to be highly context-dependentas ROS-stimulated p53 elicits inflammation through NF120581B-dependent mechanism Herein disturbed levels of both pro-and anti-inflammatory cytokines along with activated p53contribute to the exacerbation of glucose intolerance insulinresistance and elevation of serum glucose level In otherwords p53 can affect the entire organism leading to systemicdisturbances which was brilliantly visualized by pifithrin-120572 administration Consequently the remarkable emphasisshould be put on the existence of intricate and mutual regu-latory events between p53 and insulin signalling moleculesSimultaneous regulation of AKT and p53 unambiguouslyforms a core for p53-induced abnormalities Detailed mech-anistic implications of this particular interaction depend onthe phosphorylation status of specific sites located withinstructures of ATM p53 MDM2 and AKT The relationshipbetween ATM and p53 seems to be especially intriguingas obesity-associated DNA damage was found to promotep53 activity PTEN contribution to insulin resistance has alsobeen reported before [245] enriching the entire pathomech-anism by strict relationship with p53 PTEN is suggested tobe the key player of AKT-p53 crosstalk taking responsibilityfor some of the effects induced primarily by p53

Focusing further on adipose tissue it seems that p53influences its fate under physiological and pathophysiologicalconditions While it is indispensable for the functionalityof brown adipose tissue it has been revealed to suppresshypertrophy and differentiation of white adipocytes Promi-nently p53 performs senescent-like changes of adipocyteswhich can be perceived as both deepening of inflammatory


state [210] and protection against the deleterious effectsof hyperinsulinemia This becomes especially important inthe view of the mitogenic and anabolic nature of insulinactivities which are thoroughly different from the cellulareffects exhibited by p53 Thus it constitutes a great challengefor each researcher aiming to therapeutically inhibit p53 as itstotal deletion might result in the development of cancerousphenotype Nevertheless administration of pifithrin-120572 hasbeen shown to protect from weight gain even upon high fatdiet treatment

Considering the abundance of p53 activities its partici-pation in pancreatic 120573-cell apoptosis should not be perceivedas extremely unpredictable However p53 is assumed tostrengthen 120573-cell mass decrease by participation in themitochondrial-dependent apoptotic event with simultaneousavoidance of MDM2-mediated degradation Apparently p53takes advantage of its all functional capabilities in the regula-tion of glucose metabolism and insulin sensitivity

Elucidation of p53-mediated metabolic regulation isnowadays a highly developing area of research exposing itsimpact on an increasing number of prominent biochemicalprocesses All metabolic activities promoted by p53 aredirected towards suppression of oncogenesis as well as neu-tralization of effects exhibited by insulin Therefore insulinresistance seems to be an obvious consequence of the raisedlevel of p53 in obesogenic conditionsHowever an age-relatedactivity of p53 adds a new dimension to the insulin resistanceissue

While the majority of observations emphasize that p53is ubiquitously involved in the pathophysiology of insulinresistance some study results suggest that p53 protects fromobesity and diabetes Apparently its role in obesity-associateddisorders has been undervalued for too long now pointing toa strong need for further research Hopefully it might resultin the creation of new and extremely promising therapeuticapproaches However it is interesting whether p53-mediatedregulation of genes responsible for the metabolic regulationdescribed in this review is similar in the diabetes-like con-ditions Moreover interactions between p53 and microRNAnetwork merit further investigation in the diabetes-orientedresearch as they may constitute a novel idea for the devel-opment of therapeutics The abundance of p53 mediatorsand effectors do need a profound examination in order toelucidate further regulatory mechanisms controlling p53-associated actions in both tissue-specific and systemic insulinresistance Certainly the profound epigenetic research ofp53 and the components of its network would be of crucialimportance

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This paper was partially supported by the Grant from theMedical University of Lodz (no 5030-077-09503-01-002)

and Grant no 201517BNZ703019 from Polish NationalScience Centre

References

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[118] W Hu C Zhang R Wu Y Sun A Levine and Z FengldquoGlutaminase 2 a novel p53 target gene regulating energymetabolism and antioxidant functionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 107 no 16 pp 7455ndash7460 2010

[119] S Matoba J-G Kang W D Patino et al ldquop53 regulatesmitochondrial respirationrdquo Science vol 312 no 5780 pp 1650ndash1653 2006

[120] P Stambolsky L Weisz I Shats et al ldquoRegulation of AIFexpression by p53rdquo Cell Death and Differentiation vol 13 no12 pp 2140ndash2149 2006

[121] N Vahsen C Cande J-J Briere et al ldquoAIF deficiency compro-mises oxidative phosphorylationrdquo EMBO Journal vol 23 no23 pp 4679ndash4689 2004

[122] A Prokesch F A Graef T Madl et al ldquoLiver p53 is stabilizedupon starvation and required for amino acid catabolism andgluconeogenesisrdquoThe FASEB Journal 2016

[123] M Schupp F Chen E R Briggs et al ldquoMetabolite andtranscriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissuesrdquo BMC Genomics vol 14no 1 article 758 2013

[124] P Zhang B Tu H Wang et al ldquoTumor suppressor p53 coop-erates with SIRT6 to regulate gluconeogenesis by promoting


FoxO1 nuclear exclusionrdquo Proceedings of the National Academyof Sciences of the United States of America vol 111 no 29 pp10684ndash10689 2014

[125] E Sahin S CollaM Liesa et al ldquoTelomere dysfunction inducesmetabolic and mitochondrial compromiserdquo Nature vol 470no 7334 pp 359ndash365 2011

[126] S-J Wang G Yu L Jiang et al ldquoP53-dependent regulationof metabolic function through transcriptional activation ofpantothenate kinase-1 generdquo Cell Cycle vol 12 no 5 pp 753ndash761 2013

[127] T Minamino M Orimo I Shimizu et al ldquoA crucial role foradipose tissue p53 in the regulation of insulin resistancerdquoNatureMedicine vol 15 no 9 pp 1082ndash1087 2009

[128] I Goldstein K Yizhak S Madar N Goldfinger E RuppinandV Rotter ldquop53 Promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose productionrdquoCanceramp Metabolism vol 1 no 1 p 9 2013

[129] H L Armata D Golebiowski D Y Jung H J Ko J KKim and H K Sluss ldquoRequirement of the ATMp53 tumorsuppressor pathway for glucose homeostasisrdquo Molecular andCellular Biology vol 30 no 24 pp 5787ndash5794 2010

[130] D Franck L Tracy H L Armata et al ldquoGlucose tolerance inmice is linked to the dose of the p53 transactivation domainrdquoEndocrine Research vol 38 no 3 pp 139ndash150 2013

[131] R S Bar W R Levis M M Rechler et al ldquoExtreme insulinresistance in ataxia telangiectasia Defect in affinity of insulinreceptorsrdquo New England Journal of Medicine vol 298 no 21pp 1164ndash1171 1978

[132] P D Miles K Treuner M Latronica J M Olefsky and CBarlow ldquoImpaired insulin secretion in a mouse model of ataxiatelangiectasiardquo American Journal of PhysiologymdashEndocrinologyand Metabolism vol 293 no 1 pp E70ndashE74 2007

[133] S E Shoelson ldquoBanking on ATM as a new target in metabolicsyndromerdquo Cell Metabolism vol 4 no 5 pp 337ndash338 2006

[134] C Chao S Saito CW Anderson E Appella and Y Xu ldquoPhos-phorylation of murine p53 at Ser-18 regulates the p53 responsesto DNA damagerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 97 no 22 pp 11936ndash11941 2000

[135] H Kawagishi T Wakoh H Uno et al ldquoHzf regulates adipo-genesis through translational control of CEBP120572rdquo The EMBOJournal vol 27 no 10 pp 1481ndash1490 2008

[136] A J de la Torre D Rogoff and P C White ldquoP53 and cellularglucose uptakerdquo Endocrine Research vol 38 no 1 pp 32ndash392013

[137] Y Dincer S Himmetoglu S Yalin T Damci H Ilkova and TAkcay ldquoSerum levels of p53 and cytochrome c in subjects withtype 2 diabetes and impaired glucose tolerancerdquo Clinical andInvestigative Medicine vol 32 no 4 pp E266ndashE270 2009

[138] I Goldstein and V Rotter ldquoRegulation of lipid metabolismby p53mdashfighting two villains with one swordrdquo Trends inEndocrinology andMetabolism vol 23 no 11 pp 567ndash575 2012

[139] J P Hardwick ldquoCytochrome P450 omega hydroxylase (CYP4)function in fatty acid metabolism and metabolic diseasesrdquoBiochemical Pharmacology vol 75 no 12 pp 2263ndash2275 2008

[140] I Goldstein O Ezra N Rivlin et al ldquop53 a novel regulator oflipid metabolism pathwaysrdquo Journal of Hepatology vol 56 no3 pp 656ndash662 2012

[141] K Zaugg Y Yao P T Reilly et al ldquoCarnitine palmitoyl-transferase 1C promotes cell survival and tumor growth underconditions of metabolic stressrdquoGenes and Development vol 25no 10 pp 1041ndash1051 2011

[142] I Shimizu Y Yoshida T Katsuno et al ldquoP53-induced adiposetissue inflammation is critically involved in the development ofinsulin resistance in heart failurerdquo Cell Metabolism vol 15 no1 pp 51ndash64 2012

[143] B Vergoni P CornejoM Dedjani et al ldquoCO-37 les dommagesa lrsquoADNet lrsquoactivation de la voie p53 dans lrsquoadipocyte contribuentau developpement de lrsquoinflammation du tissu adipeux durantlrsquoobesiterdquo Diabetes amp Metabolism vol 42 no 1 pp A11ndashA122016

[144] W Assaily D A Rubinger K Wheaton et al ldquoROS-mediatedp53 induction of Lpin1 regulates fatty acid oxidation in responseto nutritional stressrdquoMolecular Cell vol 44 no 3 pp 491ndash5012011

[145] T Ide L Brown-Endres K Chu et al ldquoGAMT a p53-induciblemodulator of apoptosis is critical for the adaptive response tonutrient stressrdquoMolecular Cell vol 51 no 4 p 552 2013

[146] B N FinckM C Gropler Z Chen et al ldquoLipin 1 is an inducibleamplifier of the hepatic PGC-1120572PPAR120572 regulatory pathwayrdquoCell Metabolism vol 4 no 3 pp 199ndash210 2006

[147] N Sen Y K Satija and SDas ldquoPGC-1120572 a keymodulator of p53promotes cell survival upon metabolic stressrdquo Molecular Cellvol 44 no 4 pp 621ndash634 2011

[148] Y Liu Y He A Jin et al ldquoRibosomal proteinndashMdm2ndashp53pathway coordinates nutrient stress with lipid metabolism byregulating MCD and promoting fatty acid oxidationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 111 no 23 pp E2414ndashE2422 2014

[149] P Jiang W Du X Wang et al ldquoP53 regulates biosynthesisthrough direct inactivation of glucose-6-phosphate dehydroge-naserdquo Nature Cell Biology vol 13 no 3 pp 310ndash316 2011

[150] H Shimano ldquoSterol regulatory element-binding proteins(SREBPs) transcriptional regulators of lipid synthetic genesrdquoProgress in Lipid Research vol 40 no 6 pp 439ndash452 2001

[151] J B Kim and B M Spiegelman ldquoADD1SREBP1 promotesadipocyte differentiation and gene expression linked to fattyacid metabolismrdquo Genes and Development vol 10 no 9 pp1096ndash1107 1996

[152] N Yahagi H Shimano T Matsuzaka et al ldquop53 activation inadipocytes of obese micerdquo Journal of Biological Chemistry vol278 no 28 pp 25395ndash25400 2003

[153] D A Velasquez G Martınez A Romero et al ldquoThe centralsirtuin 1p53 pathway is essential for the orexigenic action ofghrelinrdquo Diabetes vol 60 no 4 pp 1177ndash1185 2011

[154] B Porteiro A Dıaz-Ruız G Martınez et al ldquoGhrelin requiresp53 to stimulate lipid storage in fat and liverrdquoEndocrinology vol154 no 10 pp 3671ndash3679 2013

[155] F Fiordaliso A Leri D Cesselli et al ldquoHyperglycemia activatesp53 and p53-regulated genes leading to myocyte cell deathrdquoDiabetes vol 50 no 10 pp 2363ndash2375 2001

[156] C Ortega-Camarillo A M Guzman-Grenfell R Garcıa-Macedo et al ldquoHyperglycemia induces apoptosis and p53mobilization to mitochondria in RINm5F cellsrdquoMolecular andCellular Biochemistry vol 281 no 1-2 pp 163ndash171 2006

[157] L A Flores-Lopez M Dıaz-Flores R Garcıa-Macedo et alldquoHigh glucose induces mitochondrial p53 phosphorylation byp38 MAPK in pancreatic RINm5F cellsrdquo Molecular BiologyReports vol 40 no 8 pp 4947ndash4958 2013

[158] B-G Raul F-L L Antonio B-G L Arturo et al ldquoHyper-glycemia promotes p53-Mdm2 interaction but reduces p53ubiquitination in RINm5F cellsrdquo Molecular and Cellular Bio-chemistry vol 405 no 1-2 pp 257ndash264 2015


[159] M Y Donath D J Gross E Cerasi and N Kaiser ldquoHypergly-cemia-induced 120573-cell apoptosis in pancreatic islets of Psam-momys obesus during development of diabetesrdquo Diabetes vol48 no 4 pp 738ndash744 1999

[160] H Yuan X Zhang X Huang et al ldquoNADPH oxidase 2-derivedreactive oxygen speciesmediate FFAs-Induced dysfunction andapoptosis of 120573-cells via JNK p38 MAPK and p53 pathwaysrdquoPLoS ONE vol 5 no 12 Article ID e15726 2010

[161] C Ortega-Camarillo L A Flores-Lopez and A Avalos-Rodriguez ldquoThe role of p53 in pancreatic 120573-cell apoptosisrdquoImmunoendocrinology vol 2 2015

[162] L A Flores-Lopez M Cruz-Lopez R GarcıaMacedo etal ldquoPhosphorylation O-N-acetylglucosaminylation and poly-ADP-ribosylation of P53 in RINm5F cells cultured in highglucoserdquo Free Radical Biology and Medicine vol 53 no 2 S95pages 2012

[163] Y Zhu T Shu Y Lin et al ldquoInhibition of the receptor foradvanced glycation endproducts (RAGE) protects pancreatic120573-cellsrdquo Biochemical and Biophysical Research Communicationsvol 404 no 1 pp 159ndash165 2011

[164] V P Singh A Bali N Singh and A S Jaggi ldquoAdvancedglycation end products and diabetic complicationsrdquo KoreanJournal of Physiology and Pharmacology vol 18 no 1 pp 1ndash142014

[165] Y Li T Zhang Q Huang et al ldquoInhibition of tumor suppressorp53 preserves glycation-serum induced pancreatic beta-celldemiserdquo Endocrine vol 54 no 2 pp 383ndash395 2016

[166] X Li K K Y Cheng Z Liu et al ldquoThe MDM2-p53-pyruvatecarboxylase signalling axis couples mitochondrial metabolismto glucose-stimulated insulin secretion in pancreatic 120573-cellsrdquoNature Communications vol 7 article 11740 2016

[167] A Hoshino M Ariyoshi Y Okawa et al ldquoInhibition of p53preserves Parkin-mediated mitophagy and pancreatic 120573-cellfunction in diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 111 no 8 pp 3116ndash3121 2014

[168] N Kon J Zhong L Qiang D Accili and W Gu ldquoInactivationof arf-bp1 induces p53 activation and diabetic phenotypes inmicerdquo Journal of Biological Chemistry vol 287 no 7 pp 5102ndash5111 2012

[169] O Tavana N Puebla-Osorio M Sang and C Zhu ldquoAbsence ofp53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in micerdquoDiabetes vol 59 no 1 pp 135ndash142 2010

[170] S Tornovsky-Babeay D Dadon O Ziv et al ldquoType 2 diabetesand congenital hyperinsulinism cause DNA double-strandbreaks and p53 activity in 120573 cellsrdquo Cell Metabolism vol 19 no 1pp 109ndash121 2014

[171] B-F Belgardt K Ahmed M Spranger et al ldquoThe microRNA-200 family regulates pancreatic beta cell survival in type 2diabetesrdquo Nature Medicine vol 21 no 6 pp 619ndash627 2015

[172] C Hinault D Kawamori CW Liew et al ldquoΔ40 isoform of p53controls 120573-cell proliferation and glucose homeostasis in micerdquoDiabetes vol 60 no 4 pp 1210ndash1222 2011

[173] AMHernandez E S Colvin Y-C Chen S LGeiss L E Ellerand P T Fueger ldquoUpregulation of p21 activates the intrinsicapoptotic pathway in 120573-cellsrdquo American Journal of PhysiologymdashEndocrinology and Metabolism vol 304 no 12 pp E1281ndash12902013

[174] J Yang W Zhang W Jiang et al ldquoP21cip-overexpressionin the mouse 120573 cells leads to the improved recovery from

streptozotocin-induced diabetesrdquo PLoS ONE vol 4 no 12Article ID e8344 2009

[175] C Mihailidou I Chatzistamou A G Papavassiliou and HKiaris ldquoRegulation of P21 during diabetes-associated stress ofthe endoplasmic reticulumrdquo Endocrine-Related Cancer vol 22no 2 pp 217ndash228 2015

[176] P Secchiero B Toffoli E Melloni C Agnoletto L Monastaand G Zauli ldquoThe MDM2 inhibitor Nutlin-3 attenuatesstreptozotocin-induced diabetes mellitus and increases serumlevel of IL-12p40rdquo Acta Diabetologica vol 50 no 6 pp 899ndash906 2013

[177] C E Wrede L M Dickson M K Lingohr I Briaud and CJ Rhodes ldquoProtein kinase BAkt prevents fatty acid-inducedapoptosis in pancreatic120573-cells (INS-1)rdquoThe Journal of BiologicalChemistry vol 277 no 51 pp 49676ndash49684 2002

[178] P Lovis E Roggli D R Laybutt et al ldquoAlterations inMicroRNAexpression contribute to fatty acid-induced pancreatic 120573-celldysfunctionrdquo Diabetes vol 57 no 10 pp 2728ndash2736 2008

[179] H Lu L Hao S Li et al ldquoElevated circulating stearic acidleads to a major lipotoxic effect on mouse pancreatic betacells in hyperlipidaemia via amiR-34a-5p-mediated PERKp53-dependent pathwayrdquo Diabetologia vol 59 no 6 pp 1247ndash12572016

[180] Y Zhou E Zhang C Berggreen et al ldquoSurvival of pancreaticbeta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathwayrdquo Human Molecular Genetics vol 21 no 1Article ID ddr454 pp 196ndash207 2012

[181] W H Kim J W Lee B Gao and M H Jung ldquoSynergistic acti-vation of JNKSAPK induced by TNF-120572 and IFN-120574 apoptosisof pancreatic 120573-cells via the p53 and ROS pathwayrdquo CellularSignalling vol 17 no 12 pp 1516ndash1532 2005

[182] S Singh V Raina P L Chavali et al ldquoRegulation of GAD65expression by SMAR1 and p53 upon Streptozotocin treatmentrdquoBMCMolecular Biology vol 13 article 28 2012

[183] M Orimo T Minamino H Miyauchi et al ldquoProtective roleof SIRT1 in diabetic vascular dysfunctionrdquo ArteriosclerosisThrombosis and Vascular Biology vol 29 no 6 pp 889ndash8942009

[184] H Chen Y Wan S Zhou et al ldquoEndothelium-specific SIRT1overexpression inhibits hyperglycemia-induced upregulation ofvascular cell senescencerdquo Science China Life Sciences vol 55 no6 pp 467ndash473 2012

[185] B Schisano G Tripathi K McGee P G McTernan andA Ceriello ldquoGlucose oscillations more than constant highglucose induce p53 activation and a metabolic memory inhuman endothelial cellsrdquo Diabetologia vol 54 no 5 pp 1219ndash1226 2011

[186] A Rosso A Balsamo R Gambino et al ldquop53 Mediates theaccelerated onset of senescence of endothelial progenitor cellsin diabetesrdquo Journal of Biological Chemistry vol 281 no 7 pp4339ndash4347 2006

[187] M Yokoyama S Okada A Nakagomi et al ldquoInhibition ofendothelial p53 improves metabolic abnormalities related todietary obesityrdquo Cell Reports vol 7 no 5 pp 1691ndash1703 2014

[188] Z Qi J He Y Zhang Y Shao and S Ding ldquoExercise trainingattenuates oxidative stress and decreases p53 protein contentin skeletal muscle of type 2 diabetic Goto-Kakizaki ratsrdquo FreeRadical Biology and Medicine vol 50 no 7 pp 794ndash800 2011

[189] J Collier ldquoNon-alcoholic fatty liver diseaserdquo Medicine vol 35no 2 pp 86ndash88 2007


[190] M Asrih and F R Jornayvaz ldquoMetabolic syndrome andnonalcoholic fatty liver disease is insulin resistance the linkrdquoMolecular and Cellular Endocrinology vol 418 part 1 pp 55ndash652015

[191] N Yahagi H Shimano T Matsuzaka et al ldquop53 Involvementin the pathogenesis of fatty liver diseaserdquo Journal of BiologicalChemistry vol 279 no 20 pp 20571ndash20575 2004

[192] A Panasiuk J Dzieciol B Panasiuk and D ProkopowiczldquoExpression of p53 Bax and Bcl-2 proteins in hepatocytes innon-alcoholic fatty liver diseaserdquo World Journal of Gastroen-terology vol 12 no 38 pp 6198ndash6202 2006

[193] G C Farrell C Z Larter J Y Hou et al ldquoApoptosis inexperimental NASH is associated with p53 activation andTRAIL receptor expressionrdquo Journal of Gastroenterology andHepatology vol 24 no 3 pp 443ndash452 2009

[194] K Tomita T Teratani T Suzuki et al ldquoP53p66Shc-mediatedsignaling contributes to the progression of non-alcoholic steato-hepatitis in humans andmicerdquo Journal of Hepatology vol 57 no4 pp 837ndash843 2012

[195] Z Derdak K A Villegas R Harb AMWu A Sousa and J RWands ldquoInhibition of p53 attenuates steatosis and liver injury ina mouse model of non-alcoholic fatty liver diseaserdquo Journal ofHepatology vol 58 no 4 pp 785ndash791 2013

[196] S Ghosh S Bhattacharyya K Rashid and P C Sil ldquoCur-cumin protects rat liver from streptozotocin-induced diabeticpathophysiology by counteracting reactive oxygen species andinhibiting the activation of p53 and MAPKs mediated stressresponse pathwaysrdquo Toxicology Reports vol 2 pp 365ndash3762015

[197] H Ning Z Sun Y Liu et al ldquoInsulin protects hepatic lipotoxi-city by regulating ER stress through the PI3KAktp53 involvedpathway independently of autophagy inhibitionrdquoNutrients vol8 no 4 article 227 2016

[198] T Kodama T Takehara H Hikita et al ldquoIncreases in p53expression induce CTGF synthesis by mouse and humanhepatocytes and result in liver fibrosis in micerdquo Journal ofClinical Investigation vol 121 no 8 pp 3343ndash3356 2011

[199] X Zhang W Duan W-N P Lee et al ldquoOverexpression of p53improves blood glucose control in an insulin resistant diabeticmouse modelrdquo Pancreas vol 45 no 7 pp 1010ndash1017 2016

[200] I Shimizu Y Yoshida J Moriya et al ldquoSemaphorin3E-inducedinflammation contributes to insulin resistance in dietary obe-sityrdquo Cell Metabolism vol 18 no 4 pp 491ndash504 2013

[201] C-Y Chen A M Abell Y S Moon and K-H KimldquoAn advanced glycation end product (AGE)-receptor forAGEs (RAGE) axis restores adipogenic potential of senescentpreadipocytes through modulation of p53 protein functionrdquoJournal of Biological Chemistry vol 287 no 53 pp 44498ndash44507 2012

[202] J K Posa S Selvaraj K N Sangeetha S K Baskaran and BS Lakshmi ldquop53 mediates impaired insulin signaling in 3T3-L1 adipocytes during hyperinsulinemiardquo Cell Biology Interna-tional vol 38 no 7 pp 818ndash824 2014

[203] Y Yoshida I Shimizu G Katsuumi et al ldquoP53-Inducedinflammation exacerbates cardiac dysfunction during pressureoverloadrdquo Journal of Molecular and Cellular Cardiology vol 85pp 183ndash198 2015

[204] H Nakamura S Matoba E Iwai-Kanai et al ldquop53 promotescardiac dysfunction in diabetic mellitus caused by excessivemitochondrial respiration-mediated reactive oxygen speciesgeneration and lipid accumulationrdquo Circulation Heart Failurevol 5 no 1 pp 106ndash115 2012

[205] S K Raut G B Singh B Rastogi et al ldquomiR-30c and miR-181asynergistically modulate p53-p21 pathway in diabetes inducedcardiac hypertrophyrdquoMolecular and Cellular Biochemistry vol417 no 1-2 pp 191ndash203 2016

[206] F Bogazzi F Raggi D Russo et al ldquoGrowth hormone is nec-essary for the p53-mediated obesity-induced insulin resistancein male C57BL6J times CBA micerdquo Endocrinology vol 154 no 11pp 4226ndash4236 2013

[207] F JOrtega JMMoreno-NavarreteDMayas et al ldquoInflamma-tion and insulin resistance exert dual effects on adipose tissuetumor protein 53 expressionrdquo International Journal of Obesityvol 38 no 5 pp 737ndash745 2014

[208] Q Huang M Liu X Du et al ldquoRole of p53 in preadipocytedifferentiationrdquo Cell Biology International vol 38 no 12 pp1384ndash1393 2014

[209] O Al-Massadi B Porteiro D Kuhlow et al ldquoPharmacologicaland genetic manipulation of p53 in brown fat at adult but notembryonic stages regulates thermogenesis and body weight inmale micerdquo Endocrinology vol 157 no 7 pp 2735ndash2749 2016

[210] A M Cypess S Lehman GWilliams et al ldquoIdentification andimportance of brown adipose tissue in adult humansrdquoThe NewEngland Journal ofMedicine vol 360 no 15 pp 1509ndash1517 2009

[211] K Chechi A C Carpentier and D Richard ldquoUnderstandingthe brown adipocyte as a contributor to energy homeostasisrdquoTrends in Endocrinology andMetabolism vol 24 no 8 pp 408ndash420 2013

[212] X Yang S Enerback and U Smith ldquoReduced expression ofFOXC2 and brown adipogenic genes in human subjects withinsulin resistancerdquoObesity Research vol 11 no 10 pp 1182ndash11912003

[213] K Almind M Manieri W I Sivitz S Cinti and C RKahn ldquoEctopic brown adipose tissue in muscle provides amechanism for differences in risk of metabolic syndrome inmicerdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 7 pp 2366ndash2371 2007

[214] A L Carey and B A Kingwell ldquoBrown adipose tissue inhumans therapeutic potential to combat obesityrdquo Pharmacol-ogy andTherapeutics vol 140 no 1 pp 26ndash33 2013

[215] A Nakatsuka JWada K Hida et al ldquoRXR antagonism inducesG0G1 cell cycle arrest and ameliorates obesity by up-regulatingthe p53ndashp21 Cip1 equation image pathway in adipocytesrdquoJournal of Pathology vol 226 no 5 pp 784ndash795 2012

[216] N Inoue N Yahagi T Yamamoto et al ldquoCyclin-dependentkinase inhibitor p21WAF1CIP1 is involved in adipocyte dif-ferentiation and hypertrophy linking to obesity and insulinresistancerdquo Journal of Biological Chemistry vol 283 no 30 pp21220ndash21229 2008

[217] R Homayounfar M Jeddi-Tehrani M Cheraghpour A Ghor-bani and H Zand ldquoRelationship of p53 accumulation inperipheral tissues of high-fat diet-induced obese rats withdecrease in metabolic and oncogenic signaling of insulinrdquoGeneral and Comparative Endocrinology vol 214 pp 134ndash1392015

[218] H Zand R Homayounfar M Cheraghpour et al ldquoObesity-induced p53 activation in insulin-dependent and independenttissues is inhibited by 120573-adrenergic agonist in diet-inducedobese ratsrdquo Life Sciences vol 147 pp 103ndash109 2016

[219] FMonickaraj S Aravind P Nandhini et al ldquoAccelerated fat cellaging links oxidative stress and insulin resistance in adipocytesrdquoJournal of Biosciences vol 38 no 1 pp 113ndash122 2013


[220] A Gonzalez-Rodrıguez J A Mas-Gutierrez M Mirasierra etal ldquoEssential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance duringagingrdquo Aging Cell vol 11 no 2 pp 284ndash296 2012

[221] J Y Jeon R L Bradley E G Kokkotou et al ldquoMCHminusminus miceare resistant to aging-associated increases in body weight andinsulin resistancerdquo Diabetes vol 55 no 2 pp 428ndash434 2006

[222] K J Gaulton C J Wilier Y Li et al ldquoComprehensive asso-ciation study of type 2 diabetes and related quantitative traitswith 222 candidate genesrdquoDiabetes vol 57 no 11 pp 3136ndash31442008

[223] L Qu B He Y Pan et al ldquoAssociation between polymorphismsin RAPGEF1 TP53 NRF1 and type 2 diabetes in Chinese Hanpopulationrdquo Diabetes Research and Clinical Practice vol 91 no2 pp 171ndash176 2011

[224] K S Burgdorf N Grarup J M Justesen et al ldquoStudies of theassociation of Arg72Pro of tumor suppressor protein p53 withtype 2 diabetes in a combined analysis of 55521 EuropeansrdquoPLoS ONE vol 6 no 1 Article ID e15813 2011

[225] A R Bonfigli C Sirolla R Testa et al ldquoThe p53 codon 72(Arg72Pro) polymorphism is associated with the degree ofinsulin resistance in type 2 diabetic subjects a cross-sectionalstudyrdquo Acta Diabetologica vol 50 no 3 pp 429ndash436 2013

[226] E Reiling V Lyssenko J M A Boer et al ldquoCodon 72polymorphism (rs1042522) of TP53 is associated with changesin diastolic blood pressure over timerdquo European Journal ofHuman Genetics vol 20 no 6 pp 696ndash700 2012

[227] F Gloria-Bottini M Banci P Saccucci A Magrini and EBottini ldquoIs there a role of p53 codon 72 polymorphism in thesusceptibility to type 2 diabetes in overweight subjects A studyin patients with cardiovascular diseasesrdquoDiabetes Research andClinical Practice vol 91 no 3 pp e64ndashe67 2011

[228] C-P Kung J I-J Leu S Basu et al ldquoThe P72R polymorphismof p53 predisposes to obesity and metabolic dysfunctionrdquo CellReports vol 14 no 10 pp 2413ndash2425 2016

[229] K Kuricova L Pacal V Dvorakova and K Kankova ldquoAssocia-tion of the Arg72Pro polymorphism in p53 with progression ofdiabetic nephropathy in T2DM subjectsrdquo Journal of NephrologyampTherapeutics vol 4 article 153 2014

[230] M L M Bitti P Saccucci F Capasso et al ldquoGenotypes ofp53 codon 72 correlate with age at onset of type 1 diabetes ina sex-specific mannerrdquo Journal of Pediatric Endocrinology andMetabolism vol 24 no 7-8 pp 437ndash439 2011

[231] E V Spitsina N Y Yakunina D A Chudakova et al ldquoThe asso-ciation of the TP53 polymorphisms Pro72Arg and C(minus594)CCwith diabetic polyneuropathy in RussianMuscovites with type 1diabetes mellitusrdquoMolecular Biology vol 41 no 6 pp 901ndash9052007

[232] D Szoke B Molnar N Solymosi et al ldquoPolymorphisms of theApoE HSD3B1 IL-1120573 and p53 genes are associated with thedevelopment of early uremic complications in diabetic patientsResults of A DNA Resequencing Array Studyrdquo InternationalJournal of Molecular Medicine vol 23 no 2 pp 217ndash227 2009

[233] S A Lim C-K Joo M S Kim and S K Chung ldquoExpressionof p53 and caspase-8 in lens epithelial cells of diabetic cataractrdquoJournal of Cataract and Refractive Surgery vol 40 no 7 pp1102ndash1108 2014

[234] A Ashida Y Kiniwa A Kobayashi K Matsumoto and ROkuyama ldquoLow p53 positivity in verrucous skin lesion indiabetic neuropathy occurring on the dorsum of the footrdquoInternational Journal of Dermatology vol 52 no 3 pp 378ndash3802013

[235] C Wu and Q Wang ldquop53microRNAs signaling in the patho-logical mechanism of Diabetic Kidney Diseaserdquo Inflammationand Cell Signaling vol 3 no 1 2016

[236] Y Morimoto Y K Bando T Shigeta A Monji and TMurohara ldquoAtorvastatin prevents ischemic limb loss in type 2diabetes role of p53rdquo Journal of Atherosclerosis andThrombosisvol 18 no 3 pp 200ndash208 2011

[237] P D Nguyen J P Tutela V DThanik et al ldquoImproved diabeticwound healing through topical silencing of p53 is associatedwith augmented vasculogenic mediatorsrdquo Wound Repair andRegeneration vol 18 no 6 pp 553ndash559 2010

[238] Y Wang X Zhao D Shi et al ldquoOverexpression of SIRT1promotes high glucose-attenuated corneal epithelial woundhealing via p53 regulation of the IGFBP3IGF-1RAKT path-wayrdquo Investigative ophthalmology amp visual science vol 54 no5 pp 3806ndash3814 2013

[239] Y Zhao Y Tan J Dai et al ldquoExacerbation of diabetes-inducedtesticular apoptosis by zinc deficiency is most likely associatedwith oxidative stress p38 MAPK activation and p53 activationin micerdquo Toxicology Letters vol 200 no 1-2 pp 100ndash106 2011

[240] N Kilarkaje and M M Al-Bader ldquoDiabetes-induced oxidativeDNA damage alters p53-p21CIP1Waf1 signaling in the rattestisrdquo Reproductive Sciences vol 22 no 1 pp 102ndash112 2015

[241] W H Tang J Stitham Y Jin et al ldquoAldose reductase-mediatedphosphorylation of p53 leads tomitochondrial dysfunction anddamage in diabetic plateletsrdquo Circulation vol 129 no 15 pp1598ndash1609 2014

[242] L Jazayeri M J Callaghan R H Grogan et al ldquoDiabetesincreases p53-mediated apoptosis following ischemiardquo Plasticand Reconstructive Surgery vol 121 no 4 pp 1135ndash1143 2008

[243] J C Florez K A Jablonski N Bayley et al ldquoTCF7L2 polymor-phisms and progression to diabetes in the Diabetes PreventionProgramrdquoThe New England Journal of Medicine vol 355 no 3pp 241ndash250 2006

[244] B F Voight L J Scott V Steinthorsdottir et al ldquoTwelvetype 2 diabetes susceptibility loci identified through large-scaleassociation analysisrdquoNature Genetics vol 42 no 7 pp 579ndash5892010

[245] Y T Lo C J Tsao IM Liu S S Liou and J T Cheng ldquoIncreaseof PTEN gene expression in insulin resistancerdquo Hormone andMetabolic Research vol 36 no 10 pp 662ndash666 2004

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


IRSppp

ppp

p

pPI3K

PIP2PIP3

PDK1

GlycogenolysisLipolysis

ProteolysisGluconeogenesis

PTEN

LipogenesisGlycogenesis

Protein synthesis

Insulin

GLUT 4vesicle

Glucose

GLUT 4Insulin

receptor

Cell growthsurvival

ShcGrb2

Sos

MAPKcascade

Cell growth

AKT

pp

p

p ppp p

120577120582PKC 120577120582

120572120572

120573120573

Figure 1 Insulin signalling pathway Upon insulin stimulation activation of insulin receptor and thus formation of many phosphotyrosineresidues do occur Binding of IRS proteins and their phosphorylation precedes recruitment of PI3K as well as subsequent PIP2phosphorylation Note that PIP3 can be converted to PIP2 through PTEN activity PDK1 gets activated upon binding to PIP3 followedby the phosphorylation of PKC 120577120582 and AKT which stimulate GLUT4 translocation towards cell membrane and therefore glucose influxPhosphorylated AKT mediates the repression of glycogenolysis lipolysis proteolysis and gluconeogenesis as well as the activation oflipogenesis glycogenesis protein synthesis and cell survival The stimulation of insulin receptor is also accompanied by binding of adaptorproteins known as Shc The subsequent binding of Grb2 and Sos proteins initiates the MAPK cascade pathway The activation of AKT andMAPK cascade results in the promotion of cell growth

[15] Insulin receptor (IR) is a tyrosine kinase receptorwhich requires dimerization and binding of insulinmoleculesfor activation This heterotetrameric receptor is madeup of 2 extracellular 120572 subunits and 2 transmembrane120573 subunits Autophosphorylation of IR results in cre-ation of many phosphotyrosine residues which serve asdocking sites for subsequent components of this signallingpathway PTP-1B (protein-tyrosine phosphatase 1B) utilizesits phosphatase activity to reverse the process of recep-tor activation thus being one of several negative regula-tors of insulin signalling [16] Multiple phosphotyrosinesallow for recruitment and phosphorylation of various sub-strate proteins where IRS (insulin-receptor substrate) pro-teins deserve special attention [17] Phosphorylated IRSsactivate and direct PI3K (phosphatidylinositol-3-kinase)to plasma membrane PI3K phosphorylates PIP2 (phos-phatidylinositol 45-bisphosphate) thereby generating PIP3(phosphatidylinositol-345-trisphosphate) PIP3 is the keylipid signalling intermediate undergoing dephosphorylationby two lipid phosphatases SHIP2 (SH2-containing inosi-tol 51015840-phosphatase-2) and PTEN (phosphatase and tensinhomolog) [18] Increased level of PIP3 activates serine thre-onine kinase PDK1 (phosphoinositide-dependent proteinkinase-1) thus allowing phosphorylation and subsequent

activation of PKBAKT (protein kinase B also known asAKT) and atypical PKC 120577120582 (protein kinase C) [19 20]Both of them increase insulin-induced glucose uptake bytriggering translocation of GLUT4 (glucose transporter 4)from intracellular vesicles to cell membrane Not only is AKTan antiapoptotic molecule [21] but also its activity results inall metabolic effects mediated by insulin [22] AKT phos-phorylates numerous downstream targets thereby repressingglycogenolysis lipolysis proteolysis and gluconeogenesisOn the other hand AKT stimulates lipogenesis glycogenesisand protein synthesis Undoubtedly insulin is a potentgrowth factor triggering cell growth and differentiation [15]Its mitogenic activity is exerted mainly through stimulationofmitogen-activated protein kinase (MAPK) cascade Insulinsignalling pathway is depicted in Figure 1

22 Insulin Resistance Insulin action is indispensable for themaintenance of energy balance It affects a large number ofkinases and enzymes during fasting and feeding periods toenable proper functioning of the entire organism Insulinresistance is the condition characterized by lowered responseof cells to circulating insulin While the precise molecularmechanism remains to be elucidated insulin resistance isalways manifested by disturbances in insulin signalling thus



3 p53 Overview








Unstressed cell



Nucleus

pp

IRSpp

p p

PI3K

PIP2PIP3

PDK1

AKTThr 308 Ser 473

MDM2

p p

MDM2

pp

p53

MDM2

p p

p53

p53 RETarget genes

Ser 186 Ser 166

Ser 186 Ser 166

Ser 186 Ser 166







RPL26

Nucleus

USP10

Stressoroccurrence

p53

p53

AKT

p53

p

p

p53 RE

PTENp53 p53

p53 p53p p

p pATMSer 1981

MDM2

p

Ser 395p

PTEN

PTEN

p53 mRNA

p53 mRNA

MDM2

MDM2

p

p

Ser 395

Ser 395

PIP3 PIP2

PDK1

ppIRS

ppPI3K

PTEN

pSer 15

Ser 15

Stressor






Cell cyclecontrol

Antioxidantdefense

p53

DNA repair Aging

White andbrown

adipogenesis

Metabolism









Gluconeogenesis

p53 Insulin












































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















3 p53 Overview








Unstressed cell



Nucleus

pp

IRSpp

p p

PI3K

PIP2PIP3

PDK1

AKTThr 308 Ser 473

MDM2

p p

MDM2

pp

p53

MDM2

p p

p53

p53 RETarget genes

Ser 186 Ser 166

Ser 186 Ser 166

Ser 186 Ser 166







RPL26

Nucleus

USP10

Stressoroccurrence

p53

p53

AKT

p53

p

p

p53 RE

PTENp53 p53

p53 p53p p

p pATMSer 1981

MDM2

p

Ser 395p

PTEN

PTEN

p53 mRNA

p53 mRNA

MDM2

MDM2

p

p

Ser 395

Ser 395

PIP3 PIP2

PDK1

ppIRS

ppPI3K

PTEN

pSer 15

Ser 15

Stressor






Cell cyclecontrol

Antioxidantdefense

p53

DNA repair Aging

White andbrown

adipogenesis

Metabolism









Gluconeogenesis

p53 Insulin












































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Unstressed cell



Nucleus

pp

IRSpp

p p

PI3K

PIP2PIP3

PDK1

AKTThr 308 Ser 473

MDM2

p p

MDM2

pp

p53

MDM2

p p

p53

p53 RETarget genes

Ser 186 Ser 166

Ser 186 Ser 166

Ser 186 Ser 166







RPL26

Nucleus

USP10

Stressoroccurrence

p53

p53

AKT

p53

p

p

p53 RE

PTENp53 p53

p53 p53p p

p pATMSer 1981

MDM2

p

Ser 395p

PTEN

PTEN

p53 mRNA

p53 mRNA

MDM2

MDM2

p

p

Ser 395

Ser 395

PIP3 PIP2

PDK1

ppIRS

ppPI3K

PTEN

pSer 15

Ser 15

Stressor






Cell cyclecontrol

Antioxidantdefense

p53

DNA repair Aging

White andbrown

adipogenesis

Metabolism









Gluconeogenesis

p53 Insulin












































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















RPL26

Nucleus

USP10

Stressoroccurrence

p53

p53

AKT

p53

p

p

p53 RE

PTENp53 p53

p53 p53p p

p pATMSer 1981

MDM2

p

Ser 395p

PTEN

PTEN

p53 mRNA

p53 mRNA

MDM2

MDM2

p

p

Ser 395

Ser 395

PIP3 PIP2

PDK1

ppIRS

ppPI3K

PTEN

pSer 15

Ser 15

Stressor






Cell cyclecontrol

Antioxidantdefense

p53

DNA repair Aging

White andbrown

adipogenesis

Metabolism









Gluconeogenesis

p53 Insulin












































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Gluconeogenesis

p53 Insulin












































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































Hyperglycemia

ATM activation

p53 stability



and activation

AKT activation

Various p53 PTMs

P38 MAPKactivation





Reduced level ofATP

Oxidative stress
















Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Liver steatosis

p21

p66Shc

Bcl2

Bcl-XL

t-Bid



Hepatocyteapoptosis

ROS



miRNA-34a

SIRT1LKB1AMPK

120573-oxidation

p53










Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Obesity

Semaphorin-plexinD



ROS



Insulin resistance

p53

Fat accumulation



p21NF120581B





















7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























7 Conclusions








Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Competing Interests


Acknowledgments



References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ReviewArticle Is p53 Involved in Tissue-Specific Insulin...

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Transcript of ReviewArticle Is p53 Involved in Tissue-Specific Insulin...