Cell Growth, Regulation and Hormones
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Transcript of Cell Growth, Regulation and Hormones
Cell Growth, Regulation and Hormones
Levels of Cell Regulation
• Intracellular– Within the individual cells
• Local Environment– Cells response to its immediate environment, including presence
of other cells• Locally acting factors from cells• Extracelular Matrix
• Systemic Regulation– Provides for integration of activities of cells distant from each
other• Endocrine system• Nervous system• Considerable overlap between these.
Intracellular Regulation
Substrate
Product
Enzyme
RegulatoryEnzyme
Covalent modificationCan be positive or negativephosphorylation is common.
Phosphatase
Reverses regulatoryenzyme effects
Product 2
Enzyme 2
Non-covalentModifiers
Local Environment
Signal
Endocrine Cell Target Cell
Hormone
Receptor
Blood Stream
Endocrine Signaling
Signal
Signaling Cell Target Cell
Hormone
Receptor
Paracrine Signaling
Diffusion
Signal
Receptor
Autocrine Signaling
Hormone
Signal
Signaling CellTarget Cell
Receptor
Juxtacrine Signaling
Membrane-boundHormone
Integrin Signaling
Signal
Target Cell
Integrin
ECM Component
BasementMembrane
Cell Cycle
Example Growth Factors
TGFEpithelium Stroma
PgE2
TGF
Paracrine
Autocrine
CellDivision
Ligand Induced Receptor Dimerization
TGF- Receptor Signaling
Receptor
Hormone
ActivationDimerization
PO4
ATP
ADP
PO4
TyrosinePhosphorylation
SignalingMoleculeAssociation
PO4
PO4ATP
ADP
SubstratePhosphorylation
Downstream SignalsCan include activationof transcription factors
G-Protein Coupled Receptor Acti
PgE2 Signaling
ReceptorAdenylate Cyclase
R R
C C
G Protein
Inactive Inactive
Inactive
Protein Kinase A
(PKA)
R = Regulatory Subunit
C = Catalytic Subunit
GDP
PgE2 Receptor Activation
ReceptorAdenylate Cyclase
G
GG
PKA-R
PKA-RPKA-CPKA-C
GTP
GTP
GDP
ATP
cAMP
cAMP
cAMP
Phosphorlation of substratesAltered enzyme activities
PgE2
PgE2 Receptor Inactivation
ReceptorAdenylate Cyclase
G
GG
PKA-R
PKA-R
PKA-C
PKA-C
GDP
PgE2
cAMP
G
AMP
Phosphosphatase
G has GTPaseActivity
A Few More Local Factors
Growth Factor Produced
IGF-IInsulin-like growth factor I
Epithelium and StromaAs well as liver, in blood.
Inhibitors
TGF-Transforming growth factor beta
Epithelium
IGF-BPsIGF Binding proteins (many)
Epithelium (some in stroma)
Steroid Hormone Mechanism of Action
SecreteBasementMembrane
Secrete Extracellular Components
Growth Factors
Matrix Metaloprotease Secretion degrade basement membrane
Cell Division
How does the mammary gland “know” when to stop growing?
Hormone Inactivation
Protease
Degradation
Degraded Hormone
Active Hormone
Inactive Hormone
Binding Protein Interaction
Binding Protein
Receptor Downregulation
SignalsSignals
Signals
Internalized Receptors
Receptor
Hormone
xxxx
xx
DegradationInternalization
Modification
often de-phosphorylation
Inhibitory Pathway Concurrently Stimulated
TGFEpithelium Stroma
TGF
CellDivision
Hormone• Chemical substance
– There are many diverse substances• Produced in one organ
– Many (all?) organs produce hormones• Transported via blood
– Now recognize other pathways too• To a distant organ
– May not be very far• Where it modifies its function
– Many different functions can be regulated by hormones
Hormone ChemistrySteroids
EstrogensProgesteroneTestosteroneAldosteroneGlucocorticoids
ProteinsInsulinGlucagonGrowth HormoneProlactinACTHOxytocinCalcitoninParathyroid hormoneMost Growth Factors
GlycoproteinsLHFSHTSHPlacntal Lactogen
Prostaglandins
Amino AcidsThyroxinT3
CatecholaminesEpinephrineNorepinephrine
Binding Equilibrium
H + R HR
Noncovalent interaction.
In equilibrium when forward and reverse rates =.
Equilibrium calculations similar to general chemistry.
Kd = concentration when 1/2 receptors occupied.
ED50 = concentration when half-maximum responses reached. NOT necessarily = Kd.
Hormone Binding
0
20
40
60
80
100
120
0.01 0.1 1 10 100 1000
[Hormone] (arbritrary)
Hor
mon
e Bo
und
(Arb
ritr
ary
Uni
ts)
Kd(50% receptors occupied)
0
20
40
60
80
100
120
0.01 0.1 1 10 100 1000
[Hormone] (arbritrary)
Resp
onse
(A
rbri
trar
y U
nits
)Hormone Response
ED50(Half-Maximum Response)
FeedbackHigher Brain
Hypothalamus
AnteriorPituitary
Thyroid
Environment
TSH
Thyroxine Body Metabolism
TRF
Neural Impulses Positive
Negative
Other Inhibitory Mechanisms• Hormone Degradation– Most hormones are degraded with a half-life of
1-30 minutes• Time for 1/2 of hormone to be degraded
• Receptor Down-regulation– Decreases response to hormone
• Stimulation of inhibitor production– Hormone can increase production of a factor
that inhibits its production or action• Ex: mammary growth factors increase production of
growth inhibitors as a feedback loop.
Hormones Affecting Mammary Gland Development or Function