S. Adi et al., Opposing early inhibitory and late stimulatory effects of insulin-like growth factor-I on myogenin gene transcription, J CELL BIOC, 78(4), 2000, pp. 617-626
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.