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 differenti ation in association with an increase in the mRNA of myogenin, a member of the MyoD family of skeletal muscle-specific transcription factors that play s an essential role in the differentiation process. However, this is a rela tively 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 th e first 24 h, we find that ICF-I inhibits myogenin gene transcription by >8 0% but has no effect on myogenin mRNA stability. Similarly, in the first 24 h, IGF-I markedly inhibits myogenin promoter activity; the sequence -145 t o -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 c onstructs lacking the sequence -1,565 to -375 of the myogenin gene. These d ata indicate that the early inhibitory and late stimulatory effects of IGF- I on myogenin expression are mediated at the level of transcription, and th at these lime-dependent, opposing effects of IGF-I on myogenin transcriptio n are mediated by distinct regions of the myogenin gene. To our knowledge, this is the first demonstration of a gene whose promoter activity is initia lly inhibited and subsequently stimulated by ICF-I. J. Cell. Biochem. 78:61 7-626, 2000. (C) 2000 Wiley-Liss, Inc.