1. Cell Growth, Regulation and Hormones

2. 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.

3. 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

4. Local Environment

5. Signal Endocrine CellTarget Cell Hormone Receptor Blood Stream Endocrine Signaling

6. Signal Signaling CellTarget Cell Hormone Receptor Paracrine Signaling Diffusion

7. Signal Receptor Autocrine Signaling Hormone

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

9. Integrin Signaling Signal Target Cell Integrin ECM Component Basement Membrane

10. Cell Cycle

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

12. Ligand Induced Receptor Dimerization

13. TGF-  Receptor Signaling

14. G-Protein Coupled Receptor Acti

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

16. 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

17. 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

18. 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)

19. Steroid Hormone Mechanism of Action

20. Secrete Basement Membrane Secrete Extracellular Components Growth Factors Matrix Metaloprotease Secretion degrade basement membrane

21. Cell Division How does the mammary gland “know” when to stop growing?

22. Hormone Inactivation Protease Degradation Degraded Hormone Active Hormone Inactive Hormone Binding Protein Interaction Binding Protein

23. Receptor Downregulation Signals Internalized Receptors Receptor Hormone x x x x x x Degradation Internalization Modification often de-phosphorylation

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

25. 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

26. 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

27. Prostaglandins Amino Acids Thyroxin T3 Catecholamines Epinephrine Norepinephrine

28. 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.

29. Hormone Binding Kd (50% receptors occupied)

30. Hormone Response ED50 (Half-Maximum Response)

31. Feedback Higher Brain Hypothalamus Anterior Pituitary Thyroid Environment TSH Thyroxine Body Metabolism TRF Neural Impulses Positive Negative

32. 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.

33. Hormones Affecting Mammary Gland Development or Function