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Molecular and Cellular Biology, November 1999, p. 7621-7629, Vol. 19, No. 11
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

Emmanuel G. Reynaud, Karine Pelpel, Martine Guillier, Marie Pierre Leibovitch, and Serge A. Leibovitch*

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.

* 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.

Molecular and Cellular Biology, November 1999, p. 7621-7629, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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