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J. Biol. Chem., Vol. 283, Issue 32, 22157-22165, August 8, 2008

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Characterization of a Novel Cardiac Isoform of the Cell Cycle-related Kinase That Is Regulated during Heart Failure^*

Hongyu Qiu, Huacheng Dai, Komal Jain, Rina Shah, Chull Hong, Jayashree Pain, Bin Tian, Dorothy E. Vatner, Stephen F. Vatner, and Christophe Depre¹

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, and the Department of Biochemistry, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103

Myocardial infarction (MI) is often followed by heart failure (HF), but the mechanisms precipitating the transition to HF remain largely unknown. A genomic profile was performed in a monkey model of MI, from the myocardium adjacent to chronic (2-month) MI followed by 3 weeks of pacing to develop HF. The transcript of the gene encoding the cell cycle-related kinase (CCRK) was down-regulated by 50% in HF heart compared with control (p < 0.05), which was confirmed by quantitative PCR. The CCRK sequence cloned from a heart library showed a conservation of the N-terminal kinase domain when compared with the "generic" isoform cloned previously but a different C-terminal half due to alternative splicing with frameshift. The homology of the cardiac sequence was 100% between mice and humans. Expression of the corresponding protein, measured upon generation of a monoclonal antibody, was limited to heart, liver, and kidney. Upon overexpression in cardiac myocytes, both isoforms promote cell growth and reduce apoptosis by chelerythrine (p < 0.05 versus control). Using a yeast two-hybrid screening, we found an interaction of the generic but not the cardiac CCRK with cyclin H and casein kinase 2. In addition, only the generic CCRK phosphorylates the cyclin-dependent kinase 2, which was accompanied by a doubling of myocytes in the S and G₂ phases of the cell cycle (p < 0.05 versus control). Therefore, the heart expresses a splice variant of CCRK, which promotes cardiac cell growth and survival; differs from the generic isoform in terms of protein-protein interactions, substrate specificity and regulation of the cell cycle; and is down-regulated significantly in HF.

Received for publication, December 22, 2007 , and in revised form, April 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL033107, HL059139, HL069752, AG027211, AG023137, HL069020, and AG014121. This work was also supported by American Heart Association Grant 0640011N. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed: Dept. of Cell Biology and Molecular Medicine, MSB G609, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103. Tel.: 973-972-8920; Fax: 973-972-7489; E-mail: deprech{at}umdnj.edu.

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				K. B. Margulies, D. P. Bednarik, and D. L. Dries Genomics, transcriptional profiling, and heart failure. J. Am. Coll. Cardiol., May 12, 2009; 53(19): 1752 - 1759. [Abstract] [Full Text] [PDF]