Effect of N-terminal modified analogs of growth hormone on collagen synthesis in avian skin fibroblasts.
Human growth hormone (hGH) inhibits alpha 1(I) collagen gene expression in cultured avian skin fibroblasts resulting in a decrease in the amount of collagenase-digestible proteins (CDP) in the medium. In addition, a synergism exists between GH and insulin-like growth factor-I (IGF-I) in their effect on CDP. Four N-terminal modified hGH analogs were tested for their ability to affect collagen metabolism in these cells. The truncated analog Des-7 hGH(R8M, D11A) was found to be a strong antagonist of the hGH-induced inhibition of the collagen synthesis but by itself did not inhibit collagen alpha 1(I) gene expression or modify the CDP appearance in the medium. Some synergism between Des-7 hGH and IGF-I was observed. The analog Met-hGH(R19H, L20P), in which Arg19 was replaced by histidine, and Leu20 by proline was only partially potent compared with the native hormone in causing inhibition of collagen gene expression, in attenuating CDP appearance in the medium, and in antagonizing hGH. However, this analog was as potent as hGH in its ability to synergize with IGF-I. The importance of His18 was assessed by testing the response to Met-hGH(H18D), in which His18 was replaced by Asp, and to Met-hGH(H18Q), in which His18 was replaced by glutamine (as in chicken GH sequence). Substitution of His18 by a negatively charged amino acid abolished all the hormone activities tested whereas substitution with glutamine restored only part of the activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Granot
I
I
Institute of Animal Science, Volcani Center, Bet Dagan, Israel.
Halevy
O
O
Tchelet
A
A
Sakal
E
E
Gertler
A
A
Vogel
T
T
Hurwitz
S
S
Pines
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D003094:Collagen / Q000096:biosynthesis*; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008969:Molecular Sequence Data; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003094:Collagen