Lecture 6 (growth hormone
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Transcript of Lecture 6 (growth hormone
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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
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ACROMEGALY
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Dwarf mice
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Amino acid sequence of bovine growth hormone
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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 120Pig APTGKDEAQQRSDVELLRFS LLLIQSWLGPVQFLSRVFTN SLVFGTSD-RVYEKLKDLEEHorse -------------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 DIFFSPig MKCRRFVESSCAFHorse ------------- 3Dog ------------- 0Mole Rat ------------- 7Man VQ--•S--G--G- 62
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Horse Elephant ManPigAlpacaOxSheep
0
1
18
01
1 5
Goat
0
Dog
0
80
Rat Mouse
2 1
1
7
0
2
Rabbit
7 3
Rhesus
1
0
Hamster0
25
50
75
100
Possum
5
11
0
Red deer
0
3
Whale
4
Rate of evolution
(substitutions/aa site/10 9 yr)
slow phase (excl. rodents) 0.21slow phase (incl. rodents) 0.28rodents 0.49ruminants (rapid phase) 3.8primates (rapid phase) 10.8
Mill
ion
ye
ars
be
fore
pre
sen
t
GROWTH HORMONE EVOLUTION
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OVINE GH-RECEPTOR HOMOLOGY MODEL
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Alternative splicing of human GH mRNA precursor
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0 20 40 6010 30 50
kbp
hGH-N hPL-L hPL-A hGH-V hPL-B
THE HUMAN GROWTH HORMONE GENE CLUSTER
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0 20 4010 30 50kbp
hGH-N hPL-L hPL-A hGH-V hPL-B
PRIMATE GROWTH HORMONE GENE CLUSTERS
slGH
Slow loris
Human
Marmoset
1 2 3 4 5 6 7 8
Capuchin ~ 35 'genes'
Pituitary GH Placental expression Expressed? Pseudogene
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Transgenic mice
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Transgenic mice - growth curves
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From: Devlin et al. Nature 371, 209 (1994)
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Electron micrograph of a somatotroph
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REGULATION OF THE HUMAN GH GENE CLUSTER
From: Ho et al TEM 15, 40-45(2004)
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HISTONE ACETYLATION IN THE HUMAN GH GENE CLUSTER
From: Ho et al (2004)
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PROLACTIN
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Amino acid sequence of bovine prolactin
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Comparison of bovine GH and prolactin sequences
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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.
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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
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EXPRESSION OF HUMAN PROLACTIN GENE
From: Ben-Jonathan et al (2002)
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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??
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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.