1 Thyroid hormone receptors regulate adipogenesis and ...

1

Thyroid hormone receptors regulate adipogenesis and carcinogenesis via cross-talk

signaling with peroxisome proliferator-activated receptors

Changxue Lu and Sheue-yann Cheng

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute,

National Institutes of Health, Bethesda, MD 20892, USA

Running head: Cross-talk of TR with PPAR signaling

‡To whom correspondence should be addressed at: Laboratory of Molecular Biology,

National Cancer Institute, 37 Convent Dr, Room 5128, Bethesda, MD 20892-4264

Tel: (301) 496-4280; Fax: (301) 480-9676; E-mail: [email protected]

of 34 Accepted Preprint first posted on 9 September 2009 as Manuscript JME-09-0107

Copyright © 2009 by the Society for Endocrinology.

mailto:[email protected]

2

Abstract

Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are

members of the nuclear receptor superfamily. They are ligand-dependent transcription factors

that interact with their cognate hormone response elements in the promoters to regulate

respective target gene expression to modulate cellular functions. While the transcription

activity of each is regulated by their respective ligands, recent studies indicate that via

multiple mechanisms PPARs and TRs cross-talk to affect diverse biological functions. Here

we review recent advances in the understanding of the molecular mechanisms and biological

impact of cross-talk between these two important nuclear receptors, focusing on their roles in

adipogenesis and carcinogenesis.

of 34

3

Introduction

Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are

ligand-dependent transcription receptors of the subfamily 1 (NR1) in the nuclear receptor

superfamily. The NR1 group also includes retinoic acid receptors (RARs), Rev-erb, RAR-

related orphan receptors (RORs), oxysterol receptors (LXRs), vitamin D3 receptors (VDRs),

and the nuclear xenobiotic receptor CAR (constitutive androstane receptor). PPARs and TRs

share a conserved DNA binding domain and exert their activity partly by heterodimerization

with a common partner, the retinoid X receptor (RXR), to regulate the transcription of target

genes. PPARs and TRs each have diverse effects on developmental and metabolic processes

as well as in diseases such as obesity, diabetes, and cancer. The first part of this review

describes current understanding of PPAR and TR biology. The second part highlights recent

advances in the understanding of molecular mechanisms underlying the PPAR-TR cross-talks,

with particular emphasis on the role of such cross-talk in metabolism and carcinogenesis.

1.1 Peroxisome proliferator-activated receptors

PPARs, which consist of PPARα (NR1C1), PPARβ/δ (NR1C2, hereafter referred to as

PPARδ), and PPARγ (NR1C3) (Figure 1), are encoded by three different genes (PPARA,

PPARD, and PPARG) located at chromosomes 22, 6, and 3, respectively. Upon ligand

binding, PPARs are recruited to peroxisome proliferator response elements (PPREs) in the

regulatory region of target genes as heterodimers with the auxiliary factor RXR. With the

PPAR/RXR heterodimers, either partner can bind cognate ligands and elicit ligand-dependent

transactivation (Kliewer, et al. 1992). The canonical PPRE contains two direct repeats of the

of 34

4

hormone response element (HRE) half site (AGGTCA) with a one base-pair spacer in

between (DR1) (Kliewer et al. 1992; Tugwood, et al. 1992).

Natural and synthetic ligands have been reported for the three PPAR isotypes

(Balakumar, et al. 2007; Bensinger and Tontonoz 2008) (Table 1 & Figure 2). For PPARα,

ligands include natural unsaturated fatty acids (FAs), leukotriene, HETEs

(hydroxyeicosatetraenoic acids), and synthetic hypolipemia-inducing such as fibrates. The

PPARδ ligands are less well known, but FAs have been suggested to be natural ligands for

this subtype of PPAR (Fyffe, et al. 2006). Recent studies identified a few more PPARδ

agonists, namely tetradecylthioacetic acid (TTA), L-165041, and GW501516 (Berger, et al.

1999; Oliver, et al. 2001; Westergaard, et al. 2001). For PPARγ, endogenous ligands include

polyunsaturated FAs, prostanoids, and oxidized FAs found in low-density lipoproteins (LDLs)

(Davies, et al. 2001; Forman, et al. 1995; Kliewer, et al. 1995). Synthetic ligands for PPARγ

include antidiabetic drugs, such as rosiglitazone and pioglitazone of the thiazolidinedione

(TZD) class. This wide variety of ligands for PPARs requires a flexible plasticity in the PPAR

ligand-binding domain (LBD), which is suggested by the PPARγ crystallized structure (Nolte,

et al. 1998).

PPARα is predominantly expressed in tissues with high turnover rates of FA

metabolism, such as liver, brown adipose tissue (BAT), heart, and kidney. The target genes of

PPARα are mainly involved in mitochondrial and peroxisomal β-oxidation of FAs and

apolipoprotein synthesis. PPARδ is ubiquitously expressed in tissues. Its target genes are

involved in FA oxidation, fuel switch, mitochondrial respiration, and thermogenesis (Barish,

et al. 2006; Furnsinn, et al. 2007). PPARγ expression is mainly found in BAT and white

adipose tissue (WAT) and, to a lesser extent, in the large intestine, retina, and some immune

of 34

5

cells (e.g., macrophage and T lymphocyte) (Harris and Phipps 2001; Ricote, et al. 1998).

Activation of PPARγ affects glucose metabolism and insulin sensitization. That PPARγ also

has a dominant role in adipogenesis is suggested by many loss-of-function studies both in vivo

and in vitro (Fajas, et al. 2001).

1.2 Thyroid hormone receptors

In humans, TRs are encoded by two genes, THRA and THRB, located at chromosomes 17 and

3, respectively. The THRA gene encodes three TRα (NR1A1) isoforms, TRα1, TRα2, and

TRα3, which differ in their carboxyl terminus as a result of alternative splicing of the primary

transcripts (Figure 1). TRα1 binds T3 and activates or represses target genes, whereas TRα2

and TRα3 do not bind T3 and may antagonize T3 action (Izumo and Mahdavi 1988; Macchia,

et al. 2001; Mitsuhashi, et al. 1988). The THRA gene also yields two truncated proteins known

as TR∆α1 and TR∆α2, which play a role in intestinal development (Chassande, et al. 1997;

Plateroti, et al. 2001). The THRB gene encodes two amino-terminal TRβ (NR1A2) protein

variants—TRβ1 and TRβ2. In rodents, the same gene also gives rise to TRβ3 and a truncated

protein TR∆β3, which lacks the DNA-binding domain (DBD) (Harvey, et al. 2007; Williams

2000).

TRs bind to thyroid hormone response elements (TREs) in target genes as homodimers

as well as heterodimers with RXR. Most naturally occurring positive TREs identified to date

include 2 repeats of the half site 5’-AGGTCA-3’, which is also shared by PPREs arranged as

a direct repeat with 4 base pairs between the two half sites (DR4). Among known TREs,

inverted repeats (also called palindromes) (e.g., GGTCATGACCTA) and everted repeats

(e.g., GACCT(N6)AGGTCA, N: any nucleotide) have also been reported (Brent, et al. 1989;

of 34

6

Farsetti, et al. 1992; Forman, et al. 1992; Glass, et al. 1988). TRs have also been shown to

heterodimerize with other nuclear receptors, such as PPARs and VDRs (Bogazzi, et al. 1994;

Schrader, et al. 1994). In the presence of PPARα, TRβ has binding affinity to a DR2 present

in the myelin proteolipid protein gene promoter but not to the classical TRE, DR4, located in

the malic enzyme gene. Upon thyroid hormone stimulation, the DR2-driven reporter gene is

activated by the TRβ-PPARα heterodimer but not by TRα-PPARα, TRα-RXRβ or TRβ-

RXRβ. Three amino acids in the D box of the DBD in TRβ are critical for this

heterodimerization. The dissimilarity of the D boxes between TRβ and TRα may be

responsible for this isoform-dependent protein interaction and the DNA binding sequence

specificity (Bogazzi et al. 1994). In humans, the DBDs of TRs and PPARs are highly

homologous. Importantly, TRs and PPARs share the same proximal box (P-box) sequence in

DBD, which is critical in sequence-specific recognition of HRE by NRs while providing

contact surface with the major groove of double-stranded DNA (Nelson, et al. 1995;

Rastinejad, et al. 1995).

Triiodothyronine (T3) is the most active form of thyroid hormone in target tissues

whereas L-thyroxine (T4) is the most abundant thyroid hormone in the blood. Deiodination of

T4 by either type I or type II 5’-deiodinase (DI or DII) in different tissues gives rise to the

more active T3 locally. Several synthetic agonists for TRs have also been developed in the

past decade (Table 1). Among them, GC-1 and KB-141 have been extensively studied and

show a higher affinity to the TRβ subtype. In animal models, these TRβ-specific agonists

decrease plasma cholesterol and triglyceride levels and induce fat loss

without apparent

adverse effects on the heart and muscles (Baxter, et al. 2004; Grover, et al. 2003).

of 34

7

Similar to PPARs, tissue-dependent distribution of TR isoforms regulates thyroid

hormone actions in target organs. Both TRα and TRβ are expressed in virtually all tissues but

the abundance varies for each isoform (Lazar 1993). TRα1 is abundantly expressed in the

skeletal muscle, heart, and brown adipose tissue whereas TRα2 mRNA is highly expressed in

the brain. TRβ1 is more expressed in the brain, liver, and kidney. TRβ2 has a more restricted

expression pattern, with major distribution in the anterior pituitary and hypothalamus (Hodin,

et al. 1989). The isoform-dependent distribution further adds to the complexity in the

regulation of T3 actions.

2. Cross-talk of PPARs and TRs in metabolism and adipogenesis

2.1 Reciprocal regulation between TRs and PPARs

As do PPARs, TRs also play important roles in lipid mobilization, lipid degradation, FA

oxidation, and glucose metabolism. By direct or indirect effect, thyroid status influences the

expression of a number of genes involved in lipid and glucose metabolism. For example, TR

isoform-specific regulation of hepatic genes involved in lipogenesis and FA oxidation has

been implicated by the cDNA array analysis of TRβ knockout mice treated

with or without

thyroid hormone (Flores-Morales, et al. 2002). Among more than 200 hepatic genes

responding to T3 treatment, approximately 60% of them are regulated by TRβ

and the

remaining 40% are regulated through TRα. PPARα is one of the T3-regulated genes (Flores-

Morales et al. 2002).

In vivo studies reveal that TR and PPAR signaling can similarly regulate some

pathways in the lipid and glucose metabolism. In corticosteroid-induced diabetic mice, a

decreased thyroid hormone level is accompanied by increased serum levels of insulin, total

of 34

8

cholesterol, triglycerides, and tissue lipid peroxidation. Interestingly, the PPARγ-agonist

rosiglitazone is able to reverse the effect of dexamethasone and to increase T3 and T4 levels

in circulation (Jatwa, et al. 2007). Moreover, in rats with a high-fat diet and in a hyperthyroid

state, administration of the PPARα agonist Wy14,643 restores glucose tolerance by enhancing

glucose-stimulated insulin secretion and relieves the effect of hyperthyroidism. These studies

suggest that activation of PPARα activity may restore the islet function affected by abnormal

T3-TR signaling (Holness, et al. 2008).

Cross-talk between TR and PPAR signaling pathways has also been implicated in the

gene expression patterns in rats fed a high-fat diet. This diet induces an expression of the

PPARα gene with a concomitant decrease in expression in the liver of RARβ, TRα1, and

TRβ1. In WAT, this diet increases the expression of PPARγ2 but reduces expression of

RARα, TRα1, and TRβ1 (Redonnet, et al. 2001). Similar results have been obtained by using

a specific PPARα inducer, bezafibrate, in rats. After a 10-day treatment with bezafibrate,

PPARα transcription is elevated with an activation of the downstream gene, acyl-CoA oxidase

(AOX), and a decrease of maximal ligand binding capacity of RARβ and TRα1/β1(Bonilla, et

al. 2001). However, no RXRα mRNA expression is altered by the treatment (Bonilla et al.

2001; Redonnet et al. 2001).

PPARs have been shown to affect the thyroid hormone functions in thermogenesis in

vivo. Administration of the PPARγ agonist rosiglitazone to male rats shifts the energy usage to

an anabolic state. Moreover, the activation of PPARγ by rosiglitazone markedly reduces

plasma thyroid hormones and mRNA levels of DI and DII in the liver and BAT, respectively.

Rosiglitazone also decreases mRNA levels of the TRα1 and TRβ in BAT and the TRα1 and

TRα2 in retroperitoneal WAT. These results explain the functions of PPARγ in up-regulating

of 34

9

thermogenesis-related genes in WAT and BAT while balancing the whole body

thermogenesis by down-regulating the transcription activity of TRs in these processes

(Festuccia, et al. 2008). Regulation of DII by PPARγ activation has also been identified in

skeletal muscle in which the expression of DII was found to be induced by PPARγ agonists,

e.g., pioglitazone. Thus, via regulation of DII expression, PPARγ provides an additional level

of regulation via modulation of thyroid hormone metabolism (Grozovsky, et al. 2009).

Studies of energy metabolism in rats show that the PPARδ expression is modulated by

T3-TR signaling. By elevating the T3 level in hypothyroid rats, the expression of

mitochondrial PPARδ in skeletal muscle is induced along with the increased mRNA level of

mitochondria protein uncoupling protein 3 (UCP3) (de Lange, et al. 2007). More recently, in a

study using transgenic mice overexpressing the putative mitochondrial T3 receptor p43 (an

A/B domain truncated form of TRα1 (Casas, et al. 1999; Wrutniak-Cabello, et al. 2001)) in

skeletal muscles, an increased protein level of PPARδ was observed (Casas, et al. 2008).

Taken together, these findings provide evidence that TR and PPAR can cross-talk by

reciprocally affecting each other’s activity.

2.2 Competition for the auxiliary factor RXR by PPAR and TR

It is reasonable to postulate that TRs and PPARs can regulate some common target genes

involved in metabolic functions. As previously mentioned, transcriptional activities of PPARs

and TRs are determined by several factors including hormone availability, relative distribution

of receptor isoforms, and the abundance of the auxiliary factor, the RXR and other

coregulators. On the bases of the sequence homology of hormone response elements (HREs)

of 34

10

and the sharing of the heterodimerization partner RXR, several mechanisms have been

proposed to understand the cross-signaling between PPARs and TRs.

An early study examined the effect of PPARδ on the binding of TRβ to TREs and

transcription activity (Meier-Heusler, et al. 1995). Via eletrophoretic mobility shift assay

(EMSA), PPARδ was shown to reduce the binding of TRβ-RXRα to TRE, but PPARδ itself

had no affinity to the TRE either as a homodimer or heterodimer with RXRα. In a

chloramphenicol-acetyl-transferase (CAT) activity assay, however, PPARδ exerted an

inhibitory effect on T3-induced transcription activation by TRβ on the TRE-CAT reporter

gene even in the presence of overexpressed RXRα protein in cells. These results suggest that

PPARδ inhibits the transcriptional activity of TR action by competing for the heterodimerized

partner RXR in the nucleus (Meier-Heusler et al. 1995).

In another report, by site-mutagenesis, a single leucine replacement by arginine at

position 433 (L433R) of PPARα was shown to be critical in the inhibition of TR action. This

L443R alteration abolishes heterodimerization of PPARα with RXR and consequently its

selective inhibitory effect on the TR action. A mutational study also supports the idea that

PPARα does not compete with TRs for binding of TREs. Mutation in the P-box of hPPARα

(C122S), which destroys the DNA binding ability of PPARα, does not affect its interference

with TR transactivation. These findings suggest that PPARα inhibits TRα transactivation by

competing with TRα for binding to the auxiliary factor RXR (Juge-Aubry, et al. 1995).

In a similar manner as PPARs, TRs also inhibit the activity of several peroxisomal FA

oxidation enzymes regulated by both of these nuclear receptors. In transgenic mice expressing

luciferase under the control of promoter of the rat peroxisomal enoyl-CoA hydratase/3-

hydroxyacyl-CoA dehydrogenase, T3 inhibits ciprofibrate-induced luciferase activity in a TR-

of 34

11

ependent fashion. EMSA analyses reveal that regulation of the PPAR action by TR is through

competition for the available RXR. Increasing the amount of RXR in cells partially reverses

the TR inhibition on PPAR action while heterodimerization-defective TR mutants lose the

inhibitory activity. These results suggest that the peroxisome proliferators- and T3-signaling

pathways converge through their common interaction with the heterodimeric partner RXR

(Chu, et al. 1995).

2.3 Competition for HRE binding by PPARs and TRs

In addition to competition for binding to the common heterodimeric partner (i.e., RXR),

TRs compete with PPARs for binding to HREs on certain target genes. EMSA analysis shows

that TRα binds to rat AOX PPRE, thus inhibiting the binding of PPAR to PPRE as

PPAR/RXRα heterodimers. However, as shown by transient transfection assays, TRα

stimulates transactivation by PPAR/RXRα heterodimers on the AOX-PPRE-luciferase

reporter gene in a T3-independent manner with unknown mechanism (Hunter, et al. 1996).

Moreover, comparison of reporter activity between wild type and DBD-mutated (C78S) TRα1

shows that TRα1 exerts a DBD-dependent, inhibitory effect on the PPAR-induced AOX gene

transcription (Miyamoto, et al. 1997).

An in vivo study using mouse models also implicates an interdependent relationship

between TRs and PPARs via competition for binding to HREs. Via affecting the mRNA

expression levels of many genes including carnitine palmitoyl-transferase Iα (CPT-Iα), AOX,

acyl-CoA dehydrogenase (ACD), male mutant mice harboring a dominant-negative P398H

mutated TRα1 manifest visceral obesity, hyperleptinemia, reduced catecholamine-stimulated

lipolysis in WAT, and hepatic steatosis (Liu, et al. 2007). In the absence of T3, wild-type

of 34

12

TRα1 and P398H mutant significantly reduce PPARα-mediated gene transcription in CPT-

PPRE-luciferase assay. However, thyroid hormone reverses the inhibition of PPARα action by

wild-type TRα but not by the P398H mutant. In vitro studies suggest that the P398H mutant

itself is able to bind PPRE and reduce PPARα binding to PPREs. It is not clear whether

P398H mutant competes with PPARα for binding to RXR. The metabolic phenotype exhibited

by P398H mutant mice is mediated in part via the unique properties of the P398H mutant

receptor in interfering with PPARα signaling (Liu et al. 2007).

2.4 TR isoform-specific regulation of PPAR signaling in lipid metabolism

The role of TR isoforms in lipid metabolism has been recently studied in vivo using a loss-of-

function approach. Mice expressing an identical mutation (denoted as PV) in the

corresponding C-terminal region of TRα1 (TRα1PV

mouse; (Kaneshige, et al. 2001)) or TRβ1

were created (TRβPV

mouse; (Kaneshige, et al. 2000)). The PV mutation was identified in a

patient with resistance to thyroid hormone (RTH) who has a frameshift mutation in the C-

terminal 14 amino acids of TRβ, resulting in a complete loss of T3 binding and transcriptional

capacity. This PV mutation exhibits potent dominant-negative activity. Compared with

TRα1PV

mice, TRβPV

mice exhibit no reduction in white adipose mass but have significant

increases in serum free FAs and total triglycerides (Ying, et al. 2007). The impaired

adipogenesis in the white adipose tissue is mediated by the repression of the expression of

PPARγ by TRα1PV, leading to the reduced expression of genes involved in lipid synthesis

(Ying et al. 2007). Thus, in the white adipose tissue, cross-talk with PPARγ signaling is TR

isoform-dependent.

of 34

13

The TR isoform-dependent cross-talk with PPARγ is not limited to the white adipose

tissue. Liver steatosis was observed in TRβPV

mice while a reduced liver mass with scarcity

of lipid drops was detected in TRα1PV

mice (Araki, et al. 2009). In the liver of TRβPV

mice,

TRβPV activates PPARγ signaling with increased expression of PPARγ and downstream

lipogenic genes. With the increased expression of the lipogenesis together with TRβPV-

mediated decreased FA β-oxidation activity, excess lipid accumulation is observed in the liver

of TRβPV

mice. In contrast, TRα1PV functions to decrease the expression of PPARγ and its

downstream lipogenic genes, leading to reduced fat mass in the liver of TRα1PV

mice (Araki

et al. 2009). These results indicate that PPARγ signaling in the liver is distinctively regulated

by TR isoforms (Araki et al. 2009). Thus, these in vivo findings highlight the differential

regulation by TR isoforms of the PPARγ signaling in lipid metabolism.

At present, the detailed molecular mechanisms by which TR isoforms mediate

differential cross-talk with PPARγ signaling in the liver and white adipose tissue are not

known. It is possible that similar to the earlier report by Bogazzi (Bogazzi, et al. 1994),

PPARγ could have selectivity in the heterodimerization with TRα or TRβ, resulting in

differential functional consequences in lipid metabolism of these two target tissues.

Alternatively, the different co-regulatory proteins in these two target tissues could play

differential modulatory roles, leading to differential regulation in lipid metabolic pathways. In

view of the importance of the cross-talk of PPARγ with TRs in the regulation of lipid

metabolism, these issues would merit additional studies in the future.

3. Cross-talk signaling of PPARs and TRs in cancers

of 34

14

3.1 PPARs in cancers

PPARs have been implicated in several cancers including colon cancer, thyroid cancer,

and pancreatic carcinoma. However, their roles in the tumorigenesis of these cancers are

controversial. Recent studies suggest that PPARδ has a role in promoting colon tumorigenesis.

Mice with PPARδ gene disruption in colonic epithelial cells have a decreased incidence of

chemical carcinogen azoxymethane-induced colon tumors (Zuo, et al. 2009). Loss of PPARδ

also suppresses the elevated expression of vascular endothelial growth factor in tumor tissue

(Zuo et al. 2009). By contrast, in PPARδ-/-

ApcMin/+

(APC: adenomatosis polyposis coli gene;

Min: multiple intestinal neoplasia) mice, colon polyp formation is significantly greater than in

ApcMin/+

mice, suggesting that PPARδ attenuates colon carcinogenesis and therefore can

function as a tumor suppressor (Harman, et al. 2004).

PPARγ has also been proposed as a tumor suppressor in colon carcinogenesis. In

primary colorectal adenocarcinomas, approximately 8% of patients contain a loss-of-function

mutation in one PPARγ allele (Sarraf, et al. 1999). PPARγ agonists can decrease premalignant

intestinal lesions in rats treated with azoxymethane (Tanaka, et al. 2001). When PPARγ is

activated in primary colon tumors and colon cancer cell lines by PPARγ agonists, these cells

appear to stop proliferation with reduced growth and altered morphology of increased

differentiation (Sarraf, et al. 1998). Moreover, in Pparg+/-

mice with azoxymethane treatment,

a greater incidence of colon cancer with an increase of β-catenin level is observed as

compared with wild-type mice (Girnun, et al. 2002). However, an oncogenic role of PPARγ in

colon cancer has also been suggested in several reports. For example, activating of PPARγ

signaling by treating ApcMin

mice with the PPARγ ligand troglitazone increases significantly

the number of colon polyps as compared with the untreated mice (Saez, et al. 1998).

of 34

15

Human pancreatic carcinoma cells express functional PPARγ that upon activation by

its ligand, troglitazone, induces growth inhibition associated with G1 cell cycle arrest

(Motomura, et al. 2000). It has been further shown that p27Kip1

can also play a key role in

mediating the inhibitory effect by troglitazone (Motomura et al. 2000). A similar effect is also

observed in human pancreatic cancer cell lines by using PPARγ ligands, 15-deoxy-∆12,14

-

prostaglandin J2 (15d-PGJ2), and ciglitazaone. That approach showed 15d-PGJ2 induces

apoptosis through activation of caspases and reduces cell invasiveness by decreasing MMP-2

and MMP-9 protein levels and activity (Hashimoto, et al. 2002). These findings raise the

possibility that PPARγ as a potential therapeutic target for treatment of human pancreatic

carcinomas.

The role of PPARγ in thyroid cancer was discovered by the identification of the fusion

gene, the paired box 8 (PAX8)-peroxisome proliferator-activated receptor-γ (PPARγ, PAX8-

PPARγ) (Kroll, et al. 2000). Chromosomal t(2;3)(q13;p25) rearrangement results in the fusion

of the thyroid transcription factor PAX8 gene to the PPARγ gene and the expression of a

dominant negative form of PPARγ1 protein (PAX8-PPARγ fusion protein, PPFP). PAX8-

PPARγ rearrangement occurs in 25-70% of follicular thyroid cancers (FTC) (Kroll et al.

2000). Immortalized human thyrocytes or thyroid cancer cell lines expressing the PPFP have

increased cell viability and growth (Espadinha, et al. 2007; Gregory Powell, et al. 2004).

Array analysis shows that the expression of PPFP in cells leads to gene expression profiles

with distinct transcriptional signature. PPFP acts to up-regulation of genes associated with

signal transduction, cell growth, and translational control. Concurrently, PPFP represses a

large number of ribosomal protein and translational associated genes (Giordano, et al. 2006;

of 34

16

Lacroix, et al. 2005; Lui, et al. 2005). However, it is poorly understood how the fusion protein

causes FTC.

More recently, a second PPARγ gene rearrangement, CREB3L2-PPARγ, was reported

in a patient with FTC. This fusion gene encodes a CREB3L2-PPARγ fusion protein that

consists of the transactivation domain of CREB3L2 and functional domains of PPARγ1.

CREB3L2-PPARγ occurs infrequently in FTC (<3% of FTC). This fusion protein induces

proliferation in primary thyroid cells, but has lost the responsiveness to the PPARγ agonists—

troglitazone and rosiglitazone (Lui, et al. 2008).

PPARδ has also been implicated in thyroid carcinogenesis. In vivo, a higher expression

level of PPARδ is associated with increased proliferation in human thyroid tumors. This

increased PPARδ can be induced by thyroid mitogen (e.g., TSH and insulin) in normal

primary thyrocytes that are cyclin E1-dependent (Zeng, et al. 2008).

3.2 TRs in cancers

T3-TR signaling has also been implicated in the tumorigenesis of the liver, breast, thyroid,

and colon. A variety of tumor cells respond to the stimulation of thyroid hormone to

proliferate in vitro or in vivo (Esquenet, et al. 1995; Iishi, et al. 1993; Short, et al. 1980; Zhou-

Li, et al. 1992). For example, thyroid hormone enhances liver cancer cell invasion by inducing

the expression of furin protein, a pro-protein convertase involved in tumor cell metastasis. The

FURIN gene contains putative TREs and Smad binding sites. Under stimulation by thyroid

hormone or the transforming growth factor β (TGFβ), FURIN expression is induced and the

increased protein level subsequently cleaves and activates matrix metalloproteinases such as

MMP2 and MMP9 to increase tumor cell mobility (Chen, et al. 2008). In xenograft models,

of 34

17

the number of metastatic foci in liver and lung is increased with overexpression of furin in

HepG2 cells. In addition, an increased T3 level in the hypothyroid severe combined

immunodeficiency (SCID) mice injected with HepG2 overexpressing TRα1 (HepG2-TRα1)

cells also leads to an increased number of metastatic foci in liver and lung (Chen et al. 2008).

An anti-tumorigenic effect of thyroid hormone has also been reported for several tumor

cell types (Ledda-Columbano, et al. 1999; Martinez-Iglesias, et al. 2009). T3 suppresses the

growth and invasiveness of several human papillary thyroid cancer cell lines overexpressing

wild-type TRβ1 by inhibition of Akt and MAPK signaling pathways (Sedliarou, et al. 2007).

The suppression by TRβ1 of growth and invasiveness has been similarly observed in

hepatocarcinoma and breast cancer cells. In responding to growth factors including epidermal

growth factor, insulin-like growth factor-I, and TGFβ, the growth of hepatic and breast tumor

cells is increased via activation of the MAPK and PI3K signaling pathways. However, an

expression of TRβ1 blocks the growth response of these tumor cells by suppressing the

MAPK and PI3K signaling pathways (Martinez-Iglesias et al. 2009).

The clinical evidence from a case-control study shows that hypothyroidism increases the

risk of hepatocellular carcinoma by two- to three-fold (Hassan, et al. 2009). Furthermore,

decreased expression of TRβ1 is also found in patients with colorectal adenoma and

adenocarcinoma. Compared with normal colon epithelium, nuclear TRβ1 is less frequently

detected in colorectal cancer and its precursor abnormalities (such as adenomas) (Horkko, et

al. 2006). The reduced levels of TRβ1 are also associated with the polypoid growth, presence

of K-ras mutations, and more advanced stages of colorectal cancers (Horkko et al. 2006). In

APC gene-deficient mice, Wnt/β-catenin signaling is activated with increased cyclin D1

expression (Hulit, et al. 2004). Interestingly, in a colon carcinoma cell line SW480 with

of 34

18

genetic mutation in the APC gene, the high transcriptional activity of cyclin D1 promoter

induced by β-catinin signaling is inhibited by overexpressing TRβ1 with the presence of T3

[77]. These studies provide evidence that T3-TR signaling play key roles in carcinogenesis.

3.3. Cross-talk signaling by PPARs and TRs in carcinogenesis

Studies described in the previous sections [see Section 2.1] provide evidence that PPARs and

TRs can reciprocally inhibit transcriptional activity of the genes involved in metabolic

regulation either by competing for binding to the HREs or to RXR. These mechanisms can

also be extended to describe the molecular basis underlying the cross-talk signaling by PPARs

and TRs in the regulation of genes involved in carcinogenesis.

Compelling evidence to indicate that PPARγ and TRβ cross-talk affects thyroid

carcinogenesis is revealed in an animal model of FTC (TRβPV/PV mice) (Suzuki, et al. 2002).

As described in Section 2.4, the TRβPV knockin mouse was initially created to model an

inheritable disease called RTH (Kaneshige et al. 2000). And indeed, TRβPV mice faithfully

recapitulate human RTH (Kaneshige et al. 2000).

Remarkably, as homozygous TRβPV (TRβPV/PV

) mice age, they spontaneously develop

FTC with a pathological progression similar to human FTC (Suzuki et al. 2002). Consistent

with the findings in human thyroid cancer (See Section 3.1), a down-regulation of the PPARγ

gene in thyroid tumors of TRβPV/PV mice is made evident by decreased mRNA and protein

levels. In vitro and in vivo findings indicate that the mutated TRβPV protein acts to inhibit the

ligand-dependent transcription of PPARγ by competitive binding to PPREs (Araki, et al.

2005; Ying, et al. 2003). Cell-based transfection studies using PPRE-containing reporters

indicate that TRβ1 acts to enhance the transcription activity of PPARγ in the presence of both

of 34

19

T3 and troglitazone. TRβPV also binds to PPRE as TRβ1 does, but due to its lack of T3

binding, TRβPV acts to interfere with the enhancing effect of TRβ1 on the transcription of

PPARγ (Ying et al. 2003). Treating TRβPV/PV mice with a PPARγ agonist, rosiglitazone,

delays tumor progression and blocks metastatic spread (Kato, et al. 2006). Moreover, when

one allele of the PPARγ gene is disrupted in TRβPV mice, progression of FTC is accelerated

(Kato et al. 2006). These data suggest that the mutated TRβPV is a dominant negative

regulator of PPARγ action. Two other PPARγ agonists, ciglitazone and 15d-PGJ2, have also

been shown to decrease viability of a thyroid cancer cell line, CGRH W-2 (Chen, et al. 2006).

These two PPARγ agonists induce apoptosis of thyroid cancer cells through the caspase 3 and

PTEN-Akt signaling cascade, and they induce necrosis via the poly (ADP-ribose) polymerase

(PARP) pathway (Chen et al. 2006).

4. Conclusions and Future Perspectives

Recent studies have indicated that PPARs and TRs can cross-talk to affect diverse cellular

functions. Evidence presented in this review reveals three possible molecular mechanisms that

may account for the cross-talk at the gene regulation level (Figure 3). Several lines of

evidence support the notion that there is direct competition between PPARs and TRs for

HRE-binding and/or partnership with RXR. Moreover, the differential binding of PPARs or

TRs on DNA may also be determined by the context of the promoter/enhancer of the target

gene. The effect of PPARs and TRs may be cooperative or opposing during the cross-talk, but

most findings suggest the latter. Cross-talk between PPARs and TRs may also be mediated

indirectly, such as a reciprocal regulation of PPAR expression by TRs or vice versa. The TR

of 34

20

action may also be regulated indirectly by PPARs, e.g., via its modulating the intermediate

enzyme genes, such as DII involved in T3 metabolism.

Recent exciting developments in the regulation of lipid metabolism and carcinogenesis

by PPARs and TRs prompted us to focus in the present review on advances in understanding

the cross-talk between PPARs and TRs. However, both PPARs and TRs have other important

cellular functions that may also converage as a result of cross-talk between these two

receptors. It is of great interest to identify other biological processes and the target genes

involved that are modulated by this mode of regulation. Furthermore, while the present

review focuses on the cross-talk of these two receptors via nucleus-initiated genomic actions,

the cross-talk may also be via nongenomic actions. The nongenomic actions of these two

receptors have recently been reported (Bergh, et al. 2005; Furuya, et al. 2007; Gardner, et al.

2005). Thus the cross-talk of PPARs and TRs could also be mediated via the nongenomic

actions. In view of these considerations, a rapid development in the understanding in the

biological processes governed by the cross-talks of these two receptors would be forthcoming.

ACKNOWLEDGMENTS

We regret any reference omissions due to length limitation. We wish to thank all colleagues

and collaborators who have contributed to the work described in this review. The present

research was supported by the Intramural Research Program of the Center for Cancer

Research, National Cancer Institute, National Institutes of Health.

of 34

21

Table 1. Ligands for PPARs and TRs

Receptors Endogenous ligands Synthetic ligands

PPARα Polyunsaturated FAs,

leukotriene B4 (LTB4),

*HETE (Kliewer, et al. 1997)

Clofibrate, fenofibrate,

bezafibrate, gemfibrozil,

ciprofibrate, Wy14,643

(Willson, et al. 2000), BMS-

687453, BMS-711939

(Mukherjee, et al. 2008)

PPARβ/δ Unsaturated or saturated

long-chain Fas, prostacyclin,

eicosanoids, *HODE

(oxidized FA) (Shureiqi, et

al. 2003)

TTA, L-165,041, GW501516

PPARγ HODE (Schopfer, et al.

2005), 15d-PGJ2 (Forman et

al. 1995; Kliewer et al. 1995),

*azPC (Davies et al. 2001),

*LNO2 (unsaturated FA)

(Schopfer et al. 2005)

Rosiglitazone, pioglitazone,

rivoglitazone, troglitazone,

giglitazone, farglitazar,

GW7845 (Willson et al.

2000)

TRα1 T4, T3 CO23 (Ocasio and Scanlan

2006)

TRβ T4, T3 GC-1, KB-141, KB2115,

MB07811 (Baxter and Webb

2009)

* HETE: hydroxyeicosatetraenoic acid; HODE: hydroxyoctadecadienoic acid; azPC:

hexadecyl azelaoyl phosphatidylcholine; LNO2, itrolinoleic acid

of 34

22

Legends:

Figure 1 Schematic representation of the structures of PPARs and TRs. A. Modular domain

structures of nuclear receptors in general. Two most conserved domains, DBD (C domain)

and LBD (E/F domain) are colored in gray and black, respectively. B. The human PPAR

homologues. Compared with the DBD of PPARα (NR1C1), sequence homology is 86% and

83% in PPARβ/δ (NR1C2) and PPARγ1/2 (NR1C3), respectively. In LBD, sequences are less

conserved with only 70% and 68% of homology for PPARβ/δ and PPARγ1/2, respectively,

using the sequence of PPARα as a reference. C. & D. Structural comparison of rat TRα

isoforms (C) and rat TRβ isoforms (D). The areas of identical shading indicate conserved

sequences among the isoforms. The three major TRα isoforms (TRα1, α/2, and α3) mainly

differ in LBD at the carboxyl-terminus; TRβ isoforms (TRβ1, β2, and β3) mainly differ in

amino terminal A/B domain.

Figure 2 Ligand structures of TRs and PPARs. Chemical structures of several representative

TR or PPAR ligands listed in Table 1 are shown.

Figure 3 Proposed molecular mechanisms in PPAR-TR cross-talk. Three major mechanisms

underlying the cross-talk of PPARs and TRs in target gene regulation are illustrated. A.

Reciprocal regulation of the PPAR and TR expression. The liganded PPAR or TR can

reciprocally affect the gene expression of the other via direct and/or indirect regulation. B.

Competition for HRE binding. TRs competitively bind to PPRE of PPAR target genes. RA:

retinoic acid. C. Competition for RXR partnership. Either TRs (i) or PPARs (ii) compete with

the other receptor for binding to RXR, resulting in decreased availability of RXR to reduce

of 34

23

the transcriptional activity of PPAR target genes shown in (i) or the transcriptional activity of

PPAR target genes shown in (ii).

of 34

24

References: Araki O, Ying H, Furuya F, Zhu X & Cheng SY 2005 Thyroid hormone receptor beta

mutants: Dominant negative regulators of peroxisome proliferator-activated receptor gamma

action. Proc Natl Acad Sci U S A 102 16251-16256.

Araki O, Ying H, Zhu XG, Willingham MC & Cheng SY 2009 Distinct dysregulation of lipid

metabolism by unliganded thyroid hormone receptor isoforms. Mol Endocrinol 23 308-315.

Balakumar P, Rose M & Singh M 2007 PPAR ligands: are they potential agents for

cardiovascular disorders? Pharmacology 80 1-10.

Barish GD, Narkar VA & Evans RM 2006 PPAR delta: a dagger in the heart of the metabolic

syndrome. J Clin Invest 116 590-597.

Baxter JD & Webb P 2009 Thyroid hormone mimetics: potential applications in

atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 8 308-320.

Baxter JD, Webb P, Grover G & Scanlan TS 2004 Selective activation of thyroid hormone

signaling pathways by GC-1: a new approach to controlling cholesterol and body weight.

Trends Endocrinol Metab 15 154-157.

Bensinger SJ & Tontonoz P 2008 Integration of metabolism and inflammation by lipid-

activated nuclear receptors. Nature 454 470-477.

Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan

CA, Hayes NS, Li Y, et al. 1999 Novel peroxisome proliferator-activated receptor (PPAR)

gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem 274 6718-

6725.

Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S & Davis PJ 2005 Integrin

alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to

activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology

146 2864-2871.

Bogazzi F, Hudson LD & Nikodem VM 1994 A novel heterodimerization partner for thyroid

hormone receptor. Peroxisome proliferator-activated receptor. J. Biol. Chem. 269 11683-

11686.

Bonilla S, Redonnet A, Noel-Suberville C, Groubet R, Pallet V & Higueret P 2001 Effect of a

pharmacological activation of PPAR on the expression of RAR and TR in rat liver. J Physiol

Biochem 57 1-8.

Brent GA, Larsen PR, Harney JW, Koenig RJ & Moore DD 1989 Functional characterization

of the rat growth hormone promoter elements required for induction by thyroid hormone with

and without a co-transfected beta type thyroid hormone receptor. J Biol Chem 264 178-182.

Casas F, Pessemesse L, Grandemange S, Seyer P, Gueguen N, Baris O, Lepourry L, Cabello

G & Wrutniak-Cabello C 2008 Overexpression of the mitochondrial T3 receptor p43 induces

a shift in skeletal muscle fiber types. PLoS One 3 e2501.

Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Wiesner RJ, Cabello G

& Wrutniak C 1999 A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1

plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19 7913-7924.

Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P, Laudet V &

Samarut J 1997 Identification of transcripts initiated from an internal promoter in the c-erbA

alpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor

activities. Mol Endocrinol 11 1278-1290.

of 34

25

Chen RN, Huang YH, Lin YC, Yeh CT, Liang Y, Chen SL & Lin KH 2008 Thyroid hormone

promotes cell invasion through activation of furin expression in human hepatoma cell lines.

Endocrinology 149 3817-3831.

Chen Y, Wang SM, Wu JC & Huang SH 2006 Effects of PPARgamma agonists on cell

survival and focal adhesions in a Chinese thyroid carcinoma cell line. J Cell Biochem 98

1021-1035.

Chu R, Madison LD, Lin Y, Kopp P, Rao MS, Jameson JL & Reddy JK 1995 Thyroid

hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation

enzymes: cross talk between peroxisome proliferator and T3 signaling pathways. Proc Natl

Acad Sci U S A 92 11593-11597.

Davies SS, Pontsler AV, Marathe GK, Harrison KA, Murphy RC, Hinshaw JC, Prestwich

GD, Hilaire AS, Prescott SM, Zimmerman GA, et al. 2001 Oxidized alkyl phospholipids are

specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists.

J Biol Chem 276 16015-16023.

de Lange P, Feola A, Ragni M, Senese R, Moreno M, Lombardi A, Silvestri E, Amat R,

Villarroya F, Goglia F, et al. 2007 Differential 3,5,3'-triiodothyronine-mediated regulation of

uncoupling protein 3 transcription: role of Fatty acids. Endocrinology 148 4064-4072.

Espadinha C, Cavaco BM & Leite V 2007 PAX8PPARgamma stimulates cell viability and

modulates expression of thyroid-specific genes in a human thyroid cell line. Thyroid 17 497-

509.

Esquenet M, Swinnen JV, Heyns W & Verhoeven G 1995 Triiodothyronine modulates

growth, secretory function and androgen receptor concentration in the prostatic carcinoma cell

line LNCaP. Mol Cell Endocrinol 109 105-111.

Fajas L, Debril MB & Auwerx J 2001 Peroxisome proliferator-activated receptor-gamma:

from adipogenesis to carcinogenesis. J Mol Endocrinol 27 1-9.

Farsetti A, Desvergne B, Hallenbeck P, Robbins J & Nikodem VM 1992 Characterization of

myelin basic protein thyroid hormone response element and its function in the context of

native and heterologous promoter. J Biol Chem 267 15784-15788.

Festuccia WT, Oztezcan S, Laplante M, Berthiaume M, Michel C, Dohgu S, Denis RG, Brito

MN, Brito NA, Miller DS, et al. 2008 Peroxisome proliferator-activated receptor-gamma-

mediated positive energy balance in the rat is associated with reduced sympathetic drive to

adipose tissues and thyroid status. Endocrinology 149 2121-2130.

Flores-Morales A, Gullberg H, Fernandez L, Stahlberg N, Lee NH, Vennstrom B & Norstedt

G 2002 Patterns of liver gene expression governed by TRbeta. Mol Endocrinol 16 1257-1268.

Forman BM, Casanova J, Raaka BM, Ghysdael J & Samuels HH 1992 Half-site spacing and

orientation determines whether thyroid hormone and retinoic acid receptors and related factors

bind to DNA response elements as monomers, homodimers, or heterodimers. Mol Endocrinol

6 429-442.

Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM & Evans RM 1995 15-Deoxy-

delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.

Cell 83 803-812.

Furnsinn C, Willson TM & Brunmair B 2007 Peroxisome proliferator-activated receptor-

delta, a regulator of oxidative capacity, fuel switching and cholesterol transport. Diabetologia

50 8-17.

of 34

26

Furuya F, Guigon CJ, Zhao L, Lu C, Hanover JA & Cheng SY 2007 Nuclear receptor

corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. Mol Cell Biol 27

6116-6126.

Fyffe SA, Alphey MS, Buetow L, Smith TK, Ferguson MA, Sorensen MD, Bjorkling F &

Hunter WN 2006 Recombinant human PPAR-beta/delta ligand-binding domain is locked in

an activated conformation by endogenous fatty acids. J Mol Biol 356 1005-1013.

Gardner OS, Dewar BJ & Graves LM 2005 Activation of Mitogen-Activated Protein Kinases

by Peroxisome Proliferator-Activated Receptor Ligands: An Example of Nongenomic

Signaling. Mol Pharmacol 68 933-941.

Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG, Jr., Vinco M, Misek

DE, Sanders D, Zhu Z, et al. 2006 Delineation, functional validation, and bioinformatic

evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG

translocation. Clin Cancer Res 12 1983-1993.

Girnun GD, Smith WM, Drori S, Sarraf P, Mueller E, Eng C, Nambiar P, Rosenberg DW,

Bronson RT, Edelmann W, et al. 2002 APC-dependent suppression of colon carcinogenesis

by PPARgamma. Proc Natl Acad Sci U S A 99 13771-13776.

Glass CK, Holloway JM, Devary OV & Rosenfeld MG 1988 The thyroid hormone receptor

binds with opposite transcriptional effects to a common sequence motif in thyroid hormone

and estrogen response elements. Cell 54 313-323.

Gregory Powell J, Wang X, Allard BL, Sahin M, Wang XL, Hay ID, Hiddinga HJ, Deshpande

SS, Kroll TG, Grebe SK, et al. 2004 The PAX8/PPARgamma fusion oncoprotein transforms

immortalized human thyrocytes through a mechanism probably involving wild-type

PPARgamma inhibition. Oncogene 23 3634-3641.

Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R,

Vennstrom B, et al. 2003 Selective thyroid hormone receptor-beta activation: a strategy for

reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability.

Proc Natl Acad Sci U S A 100 10067-10072.

Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC & Kim

BW 2009 Type 2 deiodinase expression is induced by peroxisomal proliferator-activated

receptor-gamma agonists in skeletal myocytes. Endocrinology 150 1976-1983.

Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ & Peters JM 2004 Peroxisome

proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 10 481-483.

Harris SG & Phipps RP 2001 The nuclear receptor PPAR gamma is expressed by mouse T

lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 31 1098-1105.

Harvey CB, Bassett JH, Maruvada P, Yen PM & Williams GR 2007 The rat thyroid hormone

receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-

specific actions. Endocrinology 148 1764-1773.

Hashimoto K, Ethridge RT & Evers BM 2002 Peroxisome proliferator-activated receptor

gamma ligand inhibits cell growth and invasion of human pancreatic cancer cells. Int J

Gastrointest Cancer 32 7-22.

Hassan MM, Kaseb A, Li D, Patt YZ, Vauthey JN, Thomas MB, Curley SA, Spitz MR,

Sherman SI, Abdalla EK, et al. 2009 Association between hypothyroidism and hepatocellular

carcinoma: a case-control study in the United States. Hepatology 49 1563-1570.

Hodin RA, Lazar MA, Wintman BI, Darling DS, Koenig RJ, Larsen PR, Moore DD & Chin

WW 1989 Identification of a thyroid hormone receptor that is pituitary-specific. Science 244

76-79.

of 34

27

Holness MJ, Greenwood GK, Smith ND & Sugden MC 2008 PPARalpha activation and

increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-

stimulated insulin secretion in hyperthyroidism. Am J Physiol Endocrinol Metab 295 E1380-

1389.

Horkko TT, Tuppurainen K, George SM, Jernvall P, Karttunen TJ & Makinen MJ 2006

Thyroid hormone receptor beta1 in normal colon and colorectal cancer-association with

differentiation, polypoid growth type and K-ras mutations. Int J Cancer 118 1653-1659.

Hulit J, Wang C, Li Z, Albanese C, Rao M, Di Vizio D, Shah S, Byers SW, Mahmood R,

Augenlicht LH, et al. 2004 Cyclin D1 genetic heterozygosity regulates colonic epithelial cell

differentiation and tumor number in ApcMin mice. Mol Cell Biol 24 7598-7611.

Hunter J, Kassam A, Winrow CJ, Rachubinski RA & Capone JP 1996 Crosstalk between the

thyroid hormone and peroxisome proliferator-activated receptors in regulating peroxisome

proliferator-responsive genes. Mol Cell Endocrinol 116 213-221.

Iishi H, Tatsuta M, Baba M, Yamamoto R & Taniguchi H 1993 Enhancement by thyroxine of

gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Br J

Cancer 68 515-518.

Izumo S & Mahdavi V 1988 Thyroid hormone receptor alpha isoforms generated by

alternative splicing differentially activate myosin HC gene transcription. Nature 334 539-542.

Jatwa R, Parmar HS, Panda S & Kar A 2007 Amelioration of corticosteroid-induced type 2

diabetes mellitus by rosiglitazone is possibly mediated through stimulation of thyroid function

and inhibition of tissue lipid peroxidation in mice. Basic Clin Pharmacol Toxicol 101 177-

180.

Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG & Meier

CA 1995 Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone

receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad

repeat. J Biol Chem 270 18117-18122.

Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz

DG, Wynshaw-Boris A, Refetoff S, et al. 2000 Mice with a targeted mutation in the thyroid

hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc

Natl Acad Sci U S A 97 13209-13214.

Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, Barlow C, Willingham MC &

Cheng S 2001 A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor

causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci U S A 98

15095-15100.

Kato Y, Ying H, Zhao L, Furuya F, Araki O, Willingham MC & Cheng SY 2006

PPARgamma insufficiency promotes follicular thyroid carcinogenesis via activation of the

nuclear factor-kappaB signaling pathway. Oncogene 25 2736-2747.

Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC & Lehmann JM 1995 A

prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and

promotes adipocyte differentiation. Cell 83 813-819.

Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli

W, Willson TM, Lenhard JM, et al. 1997 Fatty acids and eicosanoids regulate gene expression

through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.

Proc Natl Acad Sci U S A 94 4318-4323.

of 34

28

Kliewer SA, Umesono K, Noonan DJ, Heyman RA & Evans RM 1992 Convergence of 9-cis

retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation

of their receptors. Nature 358 771-774.

Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM & Fletcher JA 2000

PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289

1357-1360.

Lacroix L, Lazar V, Michiels S, Ripoche H, Dessen P, Talbot M, Caillou B, Levillain JP,

Schlumberger M & Bidart JM 2005 Follicular thyroid tumors with the PAX8-PPARgamma1

rearrangement display characteristic genetic alterations. Am J Pathol 167 223-231.

Lazar MA 1993 Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr

Rev 14 184-193.

Ledda-Columbano GM, Perra A, Piga R, Pibiri M, Loi R, Shinozuka H & Columbano A 1999

Cell proliferation induced by 3,3',5-triiodo-L-thyronine is associated with a reduction in the

number of preneoplastic hepatic lesions. Carcinogenesis 20 2299-2304.

Liu YY, Heymann RS, Moatamed F, Schultz JJ, Sobel D & Brent GA 2007 A mutant thyroid

hormone receptor alpha antagonizes peroxisome proliferator-activated receptor alpha

signaling in vivo and impairs fatty acid oxidation. Endocrinology 148 1206-1217.

Lui WO, Foukakis T, Liden J, Thoppe SR, Dwight T, Hoog A, Zedenius J, Wallin G, Reimers

M & Larsson C 2005 Expression profiling reveals a distinct transcription signature in

follicular thyroid carcinomas with a PAX8-PPAR(gamma) fusion oncogene. Oncogene 24

1467-1476.

Lui WO, Zeng L, Rehrmann V, Deshpande S, Tretiakova M, Kaplan EL, Leibiger I, Leibiger

B, Enberg U, Hoog A, et al. 2008 CREB3L2-PPARgamma fusion mutation identifies a

thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Res 68 7156-7164.

Macchia PE, Takeuchi Y, Kawai T, Cua K, Gauthier K, Chassande O, Seo H, Hayashi Y,

Samarut J, Murata Y, et al. 2001 Increased sensitivity to thyroid hormone in mice with

complete deficiency of thyroid hormone receptor alpha. Proc Natl Acad Sci U S A 98 349-

354.

Martinez-Iglesias O, Garcia-Silva S, Tenbaum SP, Regadera J, Larcher F, Paramio JM,

Vennstrom B & Aranda A 2009 Thyroid hormone receptor beta1 acts as a potent suppressor

of tumor invasiveness and metastasis. Cancer Res 69 501-509.

Meier-Heusler SC, Zhu X, Juge-Aubry C, Pernin A, Burger AG, Cheng SY & Meier CA 1995

Modulation of thyroid hormone action by mutant thyroid hormone receptors, c-erbA alpha 2

and peroxisome proliferator-activated receptor: evidence for different mechanisms of

inhibition. Mol Cell Endocrinol 107 55-66.

Mitsuhashi T, Tennyson GE & Nikodem VM 1988 Alternative splicing generates messages

encoding rat c-erbA proteins that do not bind thyroid hormone. Proc Natl Acad Sci U S A 85

5804-5808.

Miyamoto T, Kaneko A, Kakizawa T, Yajima H, Kamijo K, Sekine R, Hiramatsu K, Nishii Y,

Hashimoto T & Hashizume K 1997 Inhibition of peroxisome proliferator signaling pathways

by thyroid hormone receptor. Competitive binding to the response element. J Biol Chem 272

7752-7758.

Motomura W, Okumura T, Takahashi N, Obara T & Kohgo Y 2000 Activation of peroxisome

proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase

of p27KiP1 in human. Pancreatic carcinoma cells. Cancer Res 60 5558-5564.

of 34

29

Mukherjee R, Locke KT, Miao B, Meyers D, Monshizadegan H, Zhang R, Search D, Grimm

D, Flynn M, O'Malley KM, et al. 2008 Novel Peroxisome Proliferator-Activated Receptor

{alpha} Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density

Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor

Agonist. J Pharmacol Exp Ther 327 716-726.

Nelson CC, Hendy SC & Romaniuk PJ 1995 Relationship between P-box amino acid

sequence and DNA binding specificity of the thyroid hormone receptor. The effects of

sequences flanking half-sites in thyroid hormone response elements. J Biol Chem 270 16988-

16994.

Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG,

Willson TM, Glass CK & Milburn MV 1998 Ligand binding and co-activator assembly of the

peroxisome proliferator-activated receptor-gamma. Nature 395 137-143.

Ocasio CA & Scanlan TS 2006 Design and characterization of a thyroid hormone receptor

alpha (TRalpha)-specific agonist. ACS Chem Biol 1 585-593.

Oliver WR, Jr., Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC,

Winegar DA, Sznaidman ML, Lambert MH, et al. 2001 A selective peroxisome proliferator-

activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U

S A 98 5306-5311.

Plateroti M, Gauthier K, Domon-Dell C, Freund J-N, Samarut J & Chassande O 2001

Functional Interference between Thyroid Hormone Receptor {alpha} (TR{alpha}) and

Natural Truncated TR{Delta}{alpha} Isoforms in the Control of Intestine Development. Mol.

Cell. Biol. 21 4761-4772.

Rastinejad F, Perlmann T, Evans RM & Sigler PB 1995 Structural determinants of nuclear

receptor assembly on DNA direct repeats. Nature 375 203-211.

Redonnet A, Groubet R, Noel-Suberville C, Bonilla S, Martinez A & Higueret P 2001

Exposure to an obesity-inducing diet early affects the pattern of expression of peroxisome

proliferator, retinoic acid, and triiodothyronine nuclear receptors in the rat. Metabolism 50

1161-1167.

Ricote M, Li AC, Willson TM, Kelly CJ & Glass CK 1998 The peroxisome proliferator-

activated receptor-gamma is a negative regulator of macrophage activation. Nature 391 79-82.

Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA & Evans

RM 1998 Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat

Med 4 1058-1061.

Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB,

Singer S, Fletcher C, et al. 1998 Differentiation and reversal of malignant changes in colon

cancer through PPARgamma. Nat Med 4 1046-1052.

Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, de la Chapelle A,

Spiegelman BM & Eng C 1999 Loss-of-function mutations in PPAR gamma associated with

human colon cancer. Mol Cell 3 799-804.

Schopfer FJ, Lin Y, Baker PR, Cui T, Garcia-Barrio M, Zhang J, Chen K, Chen YE &

Freeman BA 2005 Nitrolinoleic acid: an endogenous peroxisome proliferator-activated

receptor gamma ligand. Proc Natl Acad Sci U S A 102 2340-2345.

Schrader M, Muller KM, Nayeri S, Kahlen JP & Carlberg C 1994 Vitamin D3-thyroid

hormone receptor heterodimer polarity directs ligand sensitivity of transactivation. Nature 370

382-386.

of 34

30

Sedliarou I, Matsuse M, Saenko V, Rogounovitch T, Nakazawa Y, Mitsutake N, Namba H,

Nagayama Y & Yamashita S 2007 Overexpression of wild-type THRbeta1 suppresses the

growth and invasiveness of human papillary thyroid cancer cells. Anticancer Res 27 3999-

4009.

Short J, Klein K, Kibert L & Ove P 1980 Involvement of the lodothyronines in liver and

hepatoma cell proliferation in the rat. Cancer Res 40 2417-2422.

Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM, Morris JS, Fan HZ, Fischer

SM & Lippman SM 2003 The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid

down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proc Natl Acad Sci

U S A 100 9968-9973.

Suzuki H, Willingham MC & Cheng SY 2002 Mice with a mutation in the thyroid hormone

receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid

carcinogenesis. Thyroid 12 963-969.

Tanaka T, Kohno H, Yoshitani S, Takashima S, Okumura A, Murakami A & Hosokawa M

2001 Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit

chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res 61 2424-

2428.

Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL & Green S 1992 The

mouse peroxisome proliferator activated receptor recognizes a response element in the 5'

flanking sequence of the rat acyl CoA oxidase gene. EMBO J 11 433-439.

Westergaard M, Henningsen J, Svendsen ML, Johansen C, Jensen UB, Schroder HD,

Kratchmarova I, Berge RK, Iversen L, Bolund L, et al. 2001 Modulation of keratinocyte gene

expression and differentiation by PPAR-selective ligands and tetradecylthioacetic acid. J

Invest Dermatol 116 702-712.

Williams GR 2000 Cloning and characterization of two novel thyroid hormone receptor beta

isoforms. Mol Cell Biol 20 8329-8342.

Willson TM, Brown PJ, Sternbach DD & Henke BR 2000 The PPARs: from orphan receptors

to drug discovery. J Med Chem 43 527-550.

Wrutniak-Cabello C, Casas F & Cabello G 2001 Thyroid hormone action in mitochondria. J

Mol Endocrinol 26 67-77.

Ying H, Araki O, Furuya F, Kato Y & Cheng SY 2007 Impaired adipogenesis caused by a

mutated thyroid hormone alpha1 receptor. Mol Cell Biol 27 2359-2371.

Ying H, Suzuki H, Zhao L, Willingham MC, Meltzer P & Cheng SY 2003 Mutant thyroid

hormone receptor beta represses the expression and transcriptional activity of peroxisome

proliferator-activated receptor gamma during thyroid carcinogenesis. Cancer Res 63 5274-

5280.

Zeng L, Geng Y, Tretiakova M, Yu X, Sicinski P & Kroll TG 2008 Peroxisome proliferator-

activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is

up-regulated in thyroid tumors. Cancer Res 68 6578-6586.

Zhou-Li F, Albaladejo V, Joly-Pharaboz MO, Nicolas B & Andre J 1992 Antiestrogens

prevent the stimulatory effects of L-triiodothyronine on cell proliferation. Endocrinology 130

1145-1152.

Zuo X, Peng Z, Moussalli MJ, Morris JS, Broaddus RR, Fischer SM & Shureiqi I 2009

Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic

tumorigenesis. J Natl Cancer Inst 101 762-767.

of 34

31

of 34

1 Thyroid hormone receptors regulate adipogenesis and ...

Health & Medicine

Transcript of 1 Thyroid hormone receptors regulate adipogenesis and ...