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