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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin. Growth hormone : general actions; receptor; signal transduction; IGFs Prolactin : actions on mammary gland; other actions; receptor; signal transduction Mechanism of action of cytokines.

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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin

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  1. MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal transduction; IGFs Prolactin: actions on mammary gland; other actions; receptor; signal transduction Mechanism of action of cytokines

  2. The GH-IGF-Somatic axis

  3. signal transmembrane 0 247 620 extracellular intracellular GH RECEPTOR • First cloned (as cDNA) from rabbit and then human liver (Leung et al 1987) Shown to be the “real” receptor by specificity, and absence in patients with Laron dwarfism

  4. Cytokine receptors

  5. OVINE GH-RECEPTOR HOMOLOGY MODEL

  6. GH-RECEPTOR INTERACTION

  7. JAK Kinases Soluble tyrosine protein kinases, first named “just another kinase”. Subsequently “janus kinases” (because two apparent binding sites for ATP) JAK1 JAK2 JAK3 Tyk

  8. GH Receptor and jak2 From: Herrington & Carter-Su (2001)

  9. GH signalling From: Herrington & Carter-Su (2001)

  10. STAT = signal transduction and activation of transcription STAT1-STAT5 In 3T3-F442A cells use of antisense knock-out of JAK2 or STAT5 eliminates GH actions. Depletion of MAPK pathway and p70s6 kinase pathway does not

  11. Regulation of GH receptor–JAK2 signaling From: Herrington & Carter-Su (2001)

  12. The GH-IGF-Somatic axis

  13. THE SULPHATION FACTOR/SOMATOMEDIN/IGF HYPOTHESIS Inject hypophysectomized rat with GH: induces growth and metabolism of cartilage (including incorporation of 35SO4 into cartilage) Incubate cartilage from hypox rat with serum from hypox rat + GH - no stimulation of cartilage metabolism Incubate cartilage from hypox rat with serum from GH-treated rat -stimulation of cartilage metabolism SO GH treatment leads to production of a factor in serum which can stimulate cartilage metabolism and growth

  14. Insulin-like growth factor I and II IGF I IGF II Somatomedins Non-suppressible-insulin-like-activity (NSILA) Multiplication stimulating activity (MSA)

  15. Sequence of IGF II

  16. Sequences of insulin and IGFs compared

  17. Precursors of insulin and IGFs proinsulin proIGF I proIGF II

  18. 3D structures of insulin and IGF IGF II Insulin

  19. The GH-IGF-Somatic axis

  20. Isaksson

  21. The GH-IGF-Somatic axis

  22. Endocrine control of mammary gland

  23. Mammary gland development

  24. Prolactin induces synthesis of the following proteins: Casein Alpha-lactalbumin Lactose synthase Fatty acid synthetase

  25. Cytokine signalling From: Shillingford et al (2001)

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