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J. Biol. Chem., Vol. 278, Issue 45, 44255-44264, November 7, 2003

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The Cell Cycle-regulated B-Myb Transcription Factor Overcomes Cyclin-dependent Kinase Inhibitory Activity of p57^KIP2 by Interacting with Its Cyclin-binding Domain^*

Manel Joaquin and Roger J. Watson

From the Ludwig Institute for Cancer Research and Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom

The cell cycle-regulated B-Myb transcription factor is required for early embryonic development and is implicated in regulating cell growth and differentiation. In addition to its transcriptional regulatory properties, recent data indicate that B-Myb can release active cyclin/Cdk2 activity from the retinoblastoma-related p107 protein by directly interacting with the p107 N terminus. As this p107 domain has homology to the cyclin-binding domains of the p21^Waf1/Cip1 family of cyclin-dependent kinase inhibitors (CKIs), we investigated in this study whether B-Myb could also interact with these CKIs. No in vivo interaction was found with either p21^Waf1/Cip1 or p27^KIP1, however, binding to p57^KIP2 was readily detectable in both in vivo and in vitro assays. The B-Myb-interacting region of p57^KIP2 mapped to the cyclin-binding domain. Consistent with this, B-Myb competed with cyclin A2 for binding to p57^KIP2, resulting in release of active cyclin/Cdk2 kinase. Moreover, B-Myb partially overcame the ability of p57^KIP2 to induce G₁ arrest in Saos-2 cells. Despite similarities with previous p107 studies, the B-Myb domains required for interaction with p57^KIP2 were quite different from those implicated for p107. Thus, it is evident that B-Myb may promote cell proliferation by a non-transcriptional mechanism that involves release of active cyclin/Cdk2 from p57^KIP2 as well as p107.

Received for publication, August 13, 2003

^* This work was supported by Cancer Research UK (Project Grant C1317/A2275). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Friedrich Miescher Institute, Maulbeerstr. 66, Basel CH-4058, Switzerland.

To whom correspondence should be addressed. Tel.: 44-20-7563-7711; Fax: 44-20-7724-8586; E-mail: r.watson{at}imperial.ac.uk.

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