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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

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Cell Growth, Regulation and Hormones

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

  4. Local Environment

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

  6. Paracrine Signaling Signaling Cell Target Cell Receptor Signal Diffusion Hormone

  7. Autocrine Signaling Hormone Signal Receptor

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

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

  10. Cell Cycle

  11. Example Growth Factors Autocrine Stroma Epithelium TGF TGF Paracrine PgE2 Cell Division

  12. Ligand Induced Receptor Dimerization

  13. TGF- Receptor Signaling

  14. G-Protein Coupled Receptor Acti

  15. PgE2 Signaling Inactive Inactive Receptor Adenylate Cyclase GDP    G Protein Inactive R R R = Regulatory Subunit Protein Kinase A (PKA) C C C = Catalytic Subunit

  16. PgE2 Receptor Activation PgE2 Receptor Adenylate Cyclase GDP GTP ATP G G G GTP cAMP cAMP PKA-C PKA-R PKA-C cAMP PKA-R Phosphorlation of substrates Altered enzyme activities

  17. PgE2 Receptor Inactivation PgE2 Receptor Adenylate Cyclase GDP G G G G G has GTPase Activity cAMP PKA-R Phosphosphatase PKA-R PKA-C PKA-C AMP

  18. A Few More Local Factors

  19. Steroid Hormone Mechanism of Action

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

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

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

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

  24. Inhibitory Pathway Concurrently Stimulated Stroma Epithelium TGF 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 Proteins Insulin Glucagon Growth Hormone Prolactin ACTH Oxytocin Calcitonin Parathyroid hormone Most Growth Factors Glycoproteins LH FSH TSH PlacntalLactogen Steroids Estrogens Progesterone Testosterone Aldosterone Glucocorticoids

  27. Amino Acids Thyroxin T3 Catecholamines Epinephrine Norepinephrine Prostaglandins

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

  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

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