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J. Biol. Chem., Vol. 279, Issue 33, 34156-34164, August 13, 2004

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Expression of the Human Myotonic Dystrophy Kinase-related Cdc42-binding Kinase Is Regulated by Promoter DNA Methylation and Sp1 Binding^*

Yvonne Ng, Ivan Tan, Louis Lim, and Thomas Leung¶

From the GSK-IMCB Group, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore and the Department of Molecular Neuroscience, Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, United Kingdom

Myotonic dystrophy kinase-related Cdc42 binding kinases (MRCKs) are family members most related to the myotonic dystrophy kinase (DMPK), RhoA-binding kinase (ROK), and citron kinase. Two highly conserved members, MRCK and -, have been previously identified and characterized. We now describe a novel isoform, MRCK, which is functionally and structurally related to members of this kinase family. We show these kinases to have marked similarities in their genomic organization, substrate phosphorylation, and catalytic autoinhibition. Unlike MRCK and -, which are expressed ubiquitously, MRCK mRNA was only expressed in heart and skeletal muscle. In cultured cells, MRCK showed differential expression with high levels of expression only in certain cell lines. DNA analysis showed that lack of expression is correlated with promoter DNA methylation. We have mapped the methylation sites in the MRCK promoter. Significantly, agents that suppressed DNA methylation caused increases in the expression of the kinase in low-expressing cells, further supporting the notion that promoter DNA methylation plays an important role in the expression of MRCK. Analysis of the MRCK promoter has also revealed two proximal Sp1 sites that are essential for transcriptional activity. We conclude that both promoter DNA methylation and Sp1 binding are important regulators for MRCK expression.

Received for publication, May 11, 2004

^* We thank the GlaxoSmithKline (Singapore) Research Fund for its support. 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.

^¶ To whom correspondence should be addressed: GSK-IMCB Group, Institute of Molecular and Cell Biology, 61 Biopolis Dr., Singapore 138673/Dept. of Anatomy, National University of Singapore, Singapore. Tel.: 65-6586-9556; Fax: 65-6774-0742; E-mail: mcbthoml{at}imcb.a-star.edu.sg.

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