Abstract
Recently, we demonstrated that okadaic acid, an inhibitor of protein phosphatases 1 and 2A, inhibits myogenesis by extinguishing the expression of MyoD1 and inducing the expression of Id. Since it has been reported that transformation by c-fos also inhibits myogenesis through inhibition of MyoD1 expression, we examined the effects of okadaic acid on the activation of the c-fos and jun family of proto-oncogenes in an attempt to understand the mechanism by which okadaic acid inhibits the myogenic differentiation. Treatment of C2C12 cells in growth medium with okadaic acid increased expression of the mRNAs for the c-fos family continuously and for the jun family to a lesser extent. In contrast, in differentiation medium, the induction of c-fos, c-jun, and fos B mRNAs by okadaic acid was transient, whereas fra-1, jun D, and jun B mRNAs were induced continuously, suggesting that okadaic acid regulates the expression of the c-fos and jun family through complex regulatory mechanisms depending on the state of differentiation of the cells. Transfection of c-jun and c-fos promoter-chloramphenicol acetyltransferase constructs demonstrated that the effects of okadaic acid on the induction of c-fos and c-jun are mediated through the activation of promoter elements. These results suggest that some of the targets of protein phosphatases 1 and 2A may include transcription factors capable of forming AP1 complexes and that these factors may play an important role during myogenic differentiation.
Highlights
We showed that okadaic acid (Suganuma et al, okadaic acid regulates the expression of thec-fos and 1988; Haystead et al, 1989; Sassa et al, 1989), a specific j u n familythroughcomplexregulatorymechanisms inhibitor of type 1and 2A protein phosphatases (Ingebritsen depending on the state of differentiation of the cells. and Cohen, 1983),blocks myogenesis byextinguishing expres
FRA-1 sion of MyoDl (Lassaret al., 1989).To examine the possibility that the inhibition of MyoDl expression by okadaic acid would correlate with the induction of the c-jun and c-fos proto-oncogenes, we analyzed the effect of okadaic acid on the expression of members of the jun and fos family in undifferentiated C2C12 myoblasts
1990; Thevenin et al, 1991) and is a potent inducer of AP1, we studied the regulation of expression of the different jun and fos genes in C2C12 myoblasts in response to okadaic acid
Summary
We showed that okadaic acid (Suganuma et al, okadaic acid regulates the expression of thec-fos and 1988; Haystead et al, 1989; Sassa et al, 1989), a specific j u n familythroughcomplexregulatorymechanisms inhibitor of type 1and 2A protein phosphatases (Ingebritsen depending on the state of differentiation of the cells. and Cohen, 1983),blocks myogenesis byextinguishing expres-. 1990; Thevenin et al, 1991) and is a potent inducer of AP1, we studied the regulation of expression of the different jun and fos genes in C2C12 myoblasts in response to okadaic acid. C2C12 cells in growth medium were treated with different concentrations of okadaic acid for 24 h, and the induction of transcripts of members of the j u n and fos families of protooncogenes in C2C12 myoblasts in growth medium.
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