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J. Biol. Chem., Vol. 280, Issue 7, 5178-5187, February 18, 2005

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MAPKAP Kinase 3pK Phosphorylates and Regulates Chromatin Association of the Polycomb Group Protein Bmi1^*

Jan Willem Voncken¶, Hanneke Niessen, Bernd Neufeld||, Ulrike Rennefahrt||, Vivian Dahlmans, Nard Kubben, Barbara Holzer, Stephan Ludwig||**, and Ulf R. Rapp||

From the Research Institute Growth and Development, Molecular Genetics, Maastricht University, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands, ^||Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Versbacher Strasse 5, D-97078 Würzburg, Germany, and ^**Institute of Molecular Virology, von Esmarchstrasse 56, D-48149 Münster, Germany

Polycomb group (PcG) proteins form chromatin-associated, transcriptionally repressive complexes, which are critically involved in the control of cell proliferation and differentiation. Although the mechanisms involved in PcG-mediated repression are beginning to unravel, little is known about the regulation of PcG function. We showed previously that PcG complexes are phosphorylated in vivo, which regulates their association with chromatin. The nature of the responsible PcG kinases remained unknown. Here we present the novel finding that the PcG protein Bmi1 is phosphorylated by 3pK (MAPKAP kinase 3), a convergence point downstream of activated ERK and p38 signaling pathways and implicated in differentiation and developmental processes. We identified 3pK as an interaction partner of PcG proteins, in vitro and in vivo, by yeast two-hybrid interaction and co-immunoprecipitation, respectively. Activation or overexpression of 3pK resulted in phosphorylation of Bmi1 and other PcG members and their dissociation from chromatin. Phosphorylation and subsequent chromatin dissociation of PcG complexes were expected to result in de-repression of targets. One such reported Bmi1 target is the Cdkn2a/INK4A locus. Cells overexpressing 3pK showed PcG complex/chromatin dissociation and concomitant de-repression of p14^ARF, which was encoded by the Cdkn2a/INK4A locus. Thus, 3pK is a candidate regulator of phosphorylation-dependent PcG/chromatin interaction. We speculate that phosphorylation may not only affect chromatin association but, in addition, the function of individual complex members. Our findings linked for the first time MAPK signaling pathways to the Polycomb transcriptional memory system. This suggests a novel mechanism by which a silenced gene status can be modulated and implicates PcG-mediated repression as a dynamically controlled process.

Received for publication, June 25, 2004 , and in revised form, November 10, 2004.

^* This work was funded by Grant 908-02-040 from the Dutch Organization for Scientific Research (NWO) (to J. W. V.) and grants from the Deutsche Forschungsgemeinschaft (DFG) (to S. L. and U. R. R.) (Lu477/7-1 and SPP1109). 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.

These authors contributed equally to this work.

^¶ To whom correspondence may be addressed. Tel.: 31433882919; Fax: 31433884574; E-mail: w.voncken{at}gen.unimaas.nl. To whom correspondence may be addressed. Tel.: 4993120145140; Fax: 499312013835; E-mail: rappur{at}mail.uni.wuerzburg.de.

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