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J. Biol. Chem., Vol. 282, Issue 33, 23919-23936, August 17, 2007

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N-terminal Truncation of Antiapoptotic MCL1, but Not G₂/M-induced Phosphorylation, Is Associated with Stabilization and Abundant Expression in Tumor Cells^*

Alfredo De Biasio¹², Julie A. Vrana¹³, Ping Zhou¹⁴, Liping Qian, Christine K. Bieszczad⁵, Karen E. Braley, Aaron M. Domina, Steven J. Weintraub^¶, John M. Neveu^||, William S. Lane^||, and Ruth W. Craig⁶

From the Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, the Department of Biology, Eastern Nazarene College, Quincy, Massachusetts 02170, the ^¶Departments of Surgery and Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri 63110, and the ^||Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, Massachusetts 02138

The antiapoptotic BCL2 family member MCL1 is normally up- and down-modulated in response to environmental signals and conditions, but is constitutively expressed in cancer where it promotes cell survival and drug resistance. A post-translational modification identified here, truncation at the N terminus, was found to act along with previously described ERK- and GSK3-induced phosphorylation events to regulate the turnover of the MCL1 protein and thus its availability for antiapoptotic effects. Although both N-terminally truncated and full-length MCL1 contain sequences enriched in proline, glutamic acid, serine, and threonine and were susceptible to proteasomal degradation, the truncated form decayed less rapidly and was maintained for an extended period in the presence of ERK activation. This was associated with extended cell survival because the truncated form of MCL1 (unlike those of BCL2 and BCLX) retained antiapoptotic activity. N-terminal truncation slightly increased the electrophoretic mobility of MCL1 and differed from the phosphorylation/band shift to decreased mobility, which occurs in the G₂/M phase and was not found to affect MCL1 turnover. The N-terminally truncated form of MCL1 was expressed to varying extents in normal lymphoid tissues and was the predominant form present in lymphomas from transgenic mice and human tumor lines of B-lymphoid origin. The degradation versus stabilized expression of antiapoptotic MCL1 is thus controlled by N-terminal truncation as well as by ERK- and GSK3 (but not G₂/M)-induced phosphorylation. These modifications may contribute to dysregulated MCL1 expression in cancer and represent targets for promoting its degradation to enhance tumor cell death.

Received for publication, January 31, 2007 , and in revised form, June 7, 2007.

^* This work was supported by Grant CA57359 from the National Institutes of Health. 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. 1 and 2.

¹ These authors contributed equally to this work.

² Present address: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

³ Present address: Mayo Clinic, Rochester, MN 55905.

⁴ Present address: Weill Medical College of Cornell University, New York, NY 10021.

⁵ Present address: St. Joseph College, West Hartford, CT 06117.

⁶ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755. Tel.: 603-650-1657; Fax: 603-650-1129; E-mail: Ruth.W.Craig{at}dartmouth.edu.

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				M. Germain and V. Duronio The N Terminus of the Anti-apoptotic BCL-2 Homologue MCL-1 Regulates Its Localization and Function J. Biol. Chem., November 2, 2007; 282(44): 32233 - 32242. [Abstract] [Full Text] [PDF]