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J. Biol. Chem., Vol. 283, Issue 17, 11565-11574, April 25, 2008

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A Novel Endogenous Human CaMKII Inhibitory Protein Suppresses Tumor Growth by Inducing Cell Cycle Arrest via p27 Stabilization^*

From the Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates numerous physiological functions. Inhibition of CaMKII activity, mostly by synthetic reagents, has been proved to suppress cell growth in many cases. So far there are no reports about the physiological functions and underlying mechanisms of endogenous CaMKII inhibitory proteins in cell cycle progression. Here we report the characterization of a novel human endogenous CaMKII inhibitor, human CaMKII inhibitory protein (hCaMKIIN), which directly interacts with activated CaMKII and effectively inhibits CaMKII activity. hCaMKIIN expression is negatively correlated with the severity of human colon adenocarcinoma. Overexpression of hCaMKIIN inhibits colon adenocarcinoma growth in vitro and in vivo by arresting the cell cycle at the S phase through its conserved inhibitory region (27CIR), whereas silencing the hCaMKIIN expression accelerates tumor growth and cell cycle progression. We found that the effect of hCaMKIIN on cell cycle is correlated with up-regulation of p27 expression, which may be due to the inhibition of proteasome degradation, but not transcriptional regulation, of p27. Moreover, hCaMKIIN deactivated MEK/ERK, which is prerequisite to the inhibition of Thr-187 phosphorylation and subsequent proteasomal degradation of p27, causing the inhibition of S-phase progression of cell cycle. The findings underscore a link between hCaMKIIN-mediated inhibition of CaMKII activity and p27-dependent pathways in controlling tumor cell growth and cell cycle and imply a potential application of hCaMKIIN in the therapeutics of colon cancers.

Received for publication, January 17, 2008 , and in revised form, February 27, 2008.

^* This work was supported by the Shanghai Committee of Science and Technology (Grant 06DJ14011), the National High Biotechnology Development Program of China (Grant 2006AA02A305), the National Natural Science Foundation of China (Grants 30570370, 30721091, and 30772504), the program for New Century Excellent Talents in University, and the Foundation for the Author of National Excellent Doctoral Dissertation of China (200462). 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 Figs. S1–S6.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Inst. of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, P.R. China. Tel.: 86 21 55620605; Fax: 86 21 6538 2502; E-mail: caoxt{at}public3.sta.net.cn.

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