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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 5/6 - Growth hormone and prolactin

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 5/6 - Growth hormone and prolactin. Growth hormone : general actions; structure; evolution; clinical applications; molecular biology, biosynthesis & secretion

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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 5/6 - Growth hormone and prolactin

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  1. MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 5/6 - Growth hormone and prolactin Growth hormone: general actions; structure; evolution; clinical applications; molecular biology, biosynthesis & secretion Prolactin: general actions; structure; the cytokine protein family; molecular biology; clinical applications; biosynthesis and secretion Placental lactogens; primates, rodents ruminants Evolution of the GH/PRL family: somatolactin

  2. ACROMEGALY

  3. Dwarf mice

  4. Amino acid sequence of bovine growth hormone

  5. AMINO ACID SEQUENCES OF SOME MAMMALIAN GROWTH HORMONES 10 20 30 40 50 60 Pig FPAMPLSSLFANAVLRAQH LHQLAADTYKEFERAYIPEG QRYS-IQNAQAAFCFSETIP Horse ------------------- -------------------- ----•--------------- Dog ------------------- -------------------- ----•--------------- Mole rat -------N----------- -------------------- ----•--------------- Man --TI---R--D--M---HR -----F---Q---E----KE -K--FL--P-TSL----S-- 70 80 90 100 110 120 Pig APTGKDEAQQRSDVELLRFS LLLIQSWLGPVQFLSRVFTN SLVFGTSD-RVYEKLKDLEE Horse -------------M------ ------------L------- --------•------R---- Dog -------------------- -------------------- --------•----------- Mole rat -----E-------M------ -------------------- --------•--F-------- Man T-SNRE-T--K-NL----I- --------E-----RS--A- ---Y-A--SN--DL------ 130 140 150 160 170 180 Pig GIQALMRELEDGSPRAGQIL KQTYDKFDTNLRSDDALLKN YGLLSCFKKDLHKAETYLRV Horse -------------------- -------------------- -------------------- Dog -------------------- -------------------- -------------------- Mole Rat -------------L----L- ----------M--------- -------------------- Man ---T--GR-------T---F ----S-----SHN------- ----Y--R--MD-V--F--I 190 DIFFS Pig MKCRRFVESSCAF Horse ------------- 3 Dog ------------- 0 Mole Rat ------------- 7 Man VQ--•S--G--G- 62

  6. GROWTH HORMONE EVOLUTION Goat Sheep Ox Red deer Alpaca Pig Whale Rabbit Horse Elephant Dog Man Rhesus Rat Mouse Hamster Possum 0 0 0 0 0 1 2 1 1 5 7 3 3 0 1 0 4 1 0 25 2 18 80 50 Million years before present 11 1 7 0 Rate of evolution 75 9 (substitutions/aa site/10 yr) slow phase (excl. rodents) 0.21 5 slow phase (incl. rodents) 0.28 rodents 0.49 ruminants (rapid phase) 3.8 primates (rapid phase) 10.8 100

  7. OVINE GH-RECEPTOR HOMOLOGY MODEL

  8. Alternative splicing of human GH mRNA precursor

  9. THE HUMAN GROWTH HORMONE GENE CLUSTER hGH-N hPL-L hPL-A hGH-V hPL-B 0 10 20 30 40 50 60 kbp

  10. PRIMATE GROWTH HORMONE GENE CLUSTERS slGH Slow loris 1 2 3 4 5 6 7 8 Marmoset Capuchin ~ 35 'genes' hGH-N hPL-L hPL-A hGH-V hPL-B Human 0 10 20 30 40 50 kbp Pituitary GH Placental expression Expressed? Pseudogene

  11. Transgenic mice

  12. Transgenic mice - growth curves

  13. From: Devlin et al. Nature 371, 209 (1994)

  14. Electron micrograph of a somatotroph

  15. REGULATION OF THE HUMAN GH GENE CLUSTER From: Ho et al TEM 15, 40-45(2004)

  16. HISTONE ACETYLATION IN THE HUMAN GH GENE CLUSTER From: Ho et al (2004)

  17. PROLACTIN

  18. Amino acid sequence of bovine prolactin

  19. Comparison of bovine GH and prolactin sequences

  20. COMPARATIVE AND EVOLUTIONARY ASPECTS OF PROLACTIN • Separate GH and prolactin found in nearly all vertebrates. GH-like molecule in jawless fish (lamprey), but no separate prolactin. No GH-like protein in invertebrates. • A third GH/prolactin-like pituitary hormone, SOMATOLACTIN, is found in many fish, but not in tetrapods? • In mammals prolactin shows variable rates of evolution. Human prolactin was identified relatively late - 1970s.

  21. SYNTHESIS AND SECRETION OF PROLACTIN • “simple precursor”: sig pept mature prolactin • single gene in humans • Synthesized and secreted from lactotrophs, under predominantly negative control from hypothalamus

  22. EXPRESSION OF HUMAN PROLACTIN GENE From: Ben-Jonathan et al (2002)

  23. CLINICAL ASPECTS OF PROLACTIN • prolactin-secreting pituitary tumours common. Can cause galactorrhoea and amenorrhoea. Treated with dopamine agonists such as bromocryptine • possible link to breast cancer??

  24. PLACENTAL LACTOGENS • In humans placental lactogen (chorionic somatomammotropin) is a GH-like protein, consequent on duplication of the GH gene • In rodents and ruminants placental lactogens are prolactin-like proteins, resulting from (independent) duplications of the prolactin gene. In both groups there are many (up to 20) prolactin-like genes, in a cluster. Their functions have not yet been fully defined.

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