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J. Biol. Chem., Vol. 282, Issue 44, 32233-32242, November 2, 2007

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The N Terminus of the Anti-apoptotic BCL-2 Homologue MCL-1 Regulates Its Localization and Function^*

From the Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, Vancouver, British Columbia V6H 3Z6, Canada

The BCL-2 homologue MCL-1 plays an important role in the regulation of cell fate by blocking apoptosis as well as regulating cell cycle. MCL-1 has an unusual N-terminal extension, which contains a PEST domain and several phosphorylation sites that have been suggested to regulate its turnover. Here we report that the first 79 amino acids of MCL-1 regulate its subcellular localization. Deletion of this domain impairs both its mitochondrial localization and its anti-apoptotic activity. Conversely, expression of the N terminus of MCL-1 promotes both the association of MCL-1 with mitochondria and cell survival in a fashion that is dependent on the presence of endogenous MCL-1. In addition, the N terminus of MCL-1 has an antagonistic effect on proliferation. Although MCL-1 decreases proliferation through binding to proliferating cell nuclear antigen and cyclin-dependent kinase 1 in the nucleus, the N terminus of MCL-1 accelerates cell division. On the other hand, deletion of this region further increases the anti-proliferative activity of MCL-1. These results suggest that the N terminus of MCL-1 plays a major regulatory role, regulating coordinately the mitochondrial (anti-apoptotic) and nuclear (anti-proliferative) functions of MCL-1.

Received for publication, August 2, 2007 , and in revised form, August 30, 2007.

^* This work was supported by a grant from the Canadian Institutes of Health Research. 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.

² Recipient of a Senior Scientist award from the Michael Smith Foundation for Health Research.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, V6H 3Z6, Canada. Tel.: 604-875-5702; Fax: 604-875-4497; E-mail: mgermain{at}interchange.ubc.ca.

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