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Molecular and Cellular Biology, November 1999, p. 7621-7629, Vol. 19, No. 11
Laboratoire de Génétique
Oncologique UMR 1599 CNRS, Institut Gustave Roussy, 94805 Villejuif,
France
Received 15 March 1999/Returned for modification 21 April
1999/Accepted 5 August 1999
We show that expression of p57Kip2, a potent
tight-binding inhibitor of several G1
cyclin-cyclin-dependent kinase (Cdk) complexes, increases markedly
during C2C12 myoblast differentiation. We examined the effect of
p57Kip2 on the activity of the transcription factor MyoD.
In transient transfection assays, transcriptional transactivation of
the mouse muscle creatine kinase promoter by MyoD was enhanced by the
Cdk inhibitors. In addition, p57Kip2, p21Cip1,
and p27Kip1 but not p16Ink4a induced an
increased level of MyoD protein, and we show that MyoD, an unstable
nuclear protein, was stabilized by p57Kip2. Forced
expression of p57Kip2 correlated with hypophosphorylation
of MyoD in C2C12 myoblasts. A dominant-negative Cdk2 mutant arrested
cells at the G1 phase transition and induced
hypophosphorylation of MyoD. Furthermore, phosphorylation of MyoD by
purified cyclin E-Cdk2 complexes was inhibited by p57Kip2.
In addition, the NH2 domain of p57Kip2 necessary for
inhibition of cyclin E-Cdk2 activity was sufficient to inhibit MyoD
phosphorylation and to stabilize it, leading to its accumulation in
proliferative myoblasts. Taken together, our data suggest that
repression of cyclin E-Cdk2-mediated phosphorylation of MyoD by
p57Kip2 could play an important role in the accumulation of
MyoD at the onset of myoblast differentiation.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
p57Kip2 Stabilizes the MyoD Protein by
Inhibiting Cyclin E-Cdk2 Kinase Activity in Growing
Myoblasts
*
Corresponding author. Mailing address: Laboratoire de
Génétique Oncologique UMR 1599 CNRS, Institut Gustave
Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France. Phone:
(33) (1) 01 42 11 45 16. Fax: (33) (1) 01 42 11 52 60. E-mail:
leibovit{at}igr.fr.
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