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 Regulatory Enzyme Covalent modification Can be positive or negative phosphorylation is common. Phosphatase Reverses regulatory enzyme effects Product 2 Enzyme 2 Non-covalent Modifiers

Local Environment

Signal Endocrine CellTarget Cell Hormone Receptor Blood Stream Endocrine Signaling

Signal Signaling CellTarget Cell Hormone Receptor Paracrine Signaling Diffusion

Signal Receptor Autocrine Signaling Hormone

Signal Signaling Cell Target Cell Receptor Juxtacrine Signaling Membrane-bound Hormone

Integrin Signaling Signal Target Cell Integrin ECM Component Basement Membrane

Cell Cycle

Example Growth Factors TGF  Epithelium Stroma PgE 2 TGF  Paracrine Autocrine Cell Division

Ligand Induced Receptor Dimerization

TGF-  Receptor Signaling

G-Protein Coupled Receptor Acti

PgE 2 Signaling Receptor Adenylate Cyclase    RR CC G Protein Inactive Protein Kinase A (PKA) R = Regulatory Subunit C = Catalytic Subunit GDP

PgE 2 Receptor Activation Receptor Adenylate Cyclase GG GG GG PKA-R PKA-C GTP GDP ATP cAMP Phosphorlation of substrates Altered enzyme activities PgE 2

PgE 2 Receptor Inactivation Receptor Adenylate Cyclase GG GG GG PKA-R PKA-C GDP PgE 2 cAMP GG AMP Phosphosphatase G  has GTPase Activity

A Few More Local Factors Growth FactorProduced IGF-I Insulin-like growth factor I Epithelium and Stroma As well as liver, in blood. Inhibitors TGF-  Transforming growth factor beta Epithelium IGF-BPs IGF Binding proteins (many) Epithelium (some in stroma)

Steroid Hormone Mechanism of Action

Secrete Basement Membrane 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 Signals Internalized Receptors Receptor Hormone x x x x x x Degradation Internalization Modification often de-phosphorylation

Inhibitory Pathway Concurrently Stimulated TGF  Epithelium Stroma TGF  Cell Division

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 Chemistry Steroids Estrogens Progesterone Testosterone Aldosterone Glucocorticoids Proteins Insulin Glucagon Growth Hormone Prolactin ACTH Oxytocin Calcitonin Parathyroid hormone Most Growth Factors Glycoproteins LH FSH TSH Placntal Lactogen

Prostaglandins Amino Acids Thyroxin T3 Catecholamines Epinephrine Norepinephrine

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 Kd (50% receptors occupied)

Hormone Response ED50 (Half-Maximum Response)

Feedback Higher Brain Hypothalamus Anterior Pituitary 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