Selective modification of human growth hormone by site-directed mutagenesis: implications for the diversity of biological actions.
Human growth hormone (GH) is an anabolic hormone required for normal growth. In addition, human GH affects the metabolism of proteins, carbohydrates and fats and possesses lactogenic effects. Although the GH receptor has recently been cloned, it is not clear whether the diverse biological activities of human GH are transduced through a single or through several types of related receptors. To address this question, 15 recombinant analogues of human GH were prepared and tested in bioassays in vitro and in vivo, in which the hormone action is mediated through lactogen or somatogen receptors. The results clearly suggest that recombinant analogues of human GH that recognize either somatogen or lactogen receptors, or both, but have selectively modified post-receptor effects, are helpful in elucidating the diverse biological activities of GH. These differences are most probably due to minor structural variability in GH and lactogen receptors in different organs and/or species. Genetic engineering of human GH may lead to production of modified analogues with changed and narrower specificities. One of the possible applications would be for a human GH analogue devoid of diabetogenic activity.
Tchelet
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Department of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel.
Gertler
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A
Sakal
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E
Djiane
J
J
Vogel
T
T
D000818:Animals; D001681:Biological Assay; D002364:Caseins / Q000096:biosynthesis; D002417:Cattle; D005260:Female; D013006:Growth Hormone / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018000:Receptors, Peptide / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002364:Caseins; D018000:Receptors, Peptide; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; C028202:placental lactogen receptor; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone