Opposing early inhibitory and late stimulatory effects of insulin-like growth factor-I on myogenin gene transcription.
Insulinlike growth factors (IGFs) stimulate skeletal muscle cell differentiation in association with an increase in the mRNA of myogenin, a member of the MyoD family of skeletal muscle-specific transcription factors that plays an essential role in the differentiation process. However, this is a relatively late effect, requiring treatment periods of >24 h. In contrast, IGFs initially inhibit skeletal muscle cell differentiation, associated with a marked reduction in myogenin mRNA. The mechanisms by which IGF-I initially inhibits and subsequently stimulates myogenin expression are unknown. In the first 24 h, we find that IGF-I inhibits myogenin gene transcription by >80% but has no effect on myogenin mRNA stability. Similarly, in the first 24 h, IGF-I markedly inhibits myogenin promoter activity; the sequence -145 to -9 of the myogenin gene is sufficient to confer this inhibitory effect of IGF-I. In contrast, 48 h of treatment with IGF-I results in an increase in myogenin promoter activity that parallels the increase in myogenin steady-state mRNA. This increase in promoter activity is completely prevented in constructs lacking the sequence -1,565 to -375 of the myogenin gene. These data indicate that the early inhibitory and late stimulatory effects of IGF-I on myogenin expression are mediated at the level of transcription, and that these time-dependent, opposing effects of IGF-I on myogenin transcription are mediated by distinct regions of the myogenin gene. To our knowledge, this is the first demonstration of a gene whose promoter activity is initially inhibited and subsequently stimulated by IGF-I.
Adi
S
S
Department of Pediatrics, University of California, San Francisco, CA 94143-0434, USA.
Cheng
Z Q
ZQ
Zhang
P L
PL
Wu
N Y
NY
Mellon
S H
SH
Rosenthal
S M
SM
D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000166:cytology; D018008:Myogenin / Q000235:genetics* / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
C503803:Myog protein, rat; D018008:Myogenin; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D007334:Insulin-Like Growth Factor I