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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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The GH-IGF-Somatic axis
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GH RECEPTOR First cloned (as cDNA) from rabbit and then human liver (Leung et al 1987) signal extracellular transmembrane intracellular 0 247620 Shown to be the real receptor by specificity, and absence in patients with Laron dwarfism
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Cytokine receptors
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OVINE GH-RECEPTOR HOMOLOGY MODEL
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GH-RECEPTOR INTERACTION
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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
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GH Receptor and jak2 From: Herrington & Carter-Su (2001)
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GH signalling From: Herrington & Carter-Su (2001)
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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 p70 s6 kinase pathway does not
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Regulation of GH receptor–JAK2 signaling From: Herrington & Carter-Su (2001)
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The GH-IGF-Somatic axis
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THE SULPHATION FACTOR/SOMATOMEDIN/IGF HYPOTHESIS Inject hypophysectomized rat with GH: induces growth and metabolism of cartilage (including incorporation of 35 SO 4 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
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Insulin-like growth factor I and II IGF I IGF II Somatomedins Non-suppressible-insulin-like-activity (NSILA) Multiplication stimulating activity (MSA)
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Sequence of IGF II
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Sequences of insulin and IGFs compared
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Precursors of insulin and IGFs proinsulin proIGF I proIGF II
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IGF IIInsulin 3D structures of insulin and IGF
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The GH-IGF-Somatic axis
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Isaksson
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The GH-IGF-Somatic axis
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Endocrine control of mammary gland
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Mammary gland development
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Prolactin induces synthesis of the following proteins: Casein Alpha-lactalbumin Lactose synthase Fatty acid synthetase
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Cytokine signalling From: Shillingford et al (2001)
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