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J. Biol. Chem. 282 (1): 5-13

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

BCL2 Is a Downstream Effector of MIZ-1 Essential for Blocking c-MYC-induced Apoptosis*

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Jagruti H. Patel{ddagger}1, and Steven B. McMahon§2

{ddagger}Biomedical Graduate Studies, University of Pennsylvania and §The Wistar Institute, Philadelphia, Pennsylvania 19104

Abstract: The c-MYC oncoprotein is among the most potent transforming agents in human cells. Ironically, c-MYC is also capable of inducing massive apoptosis under certain conditions. A clear understanding of the distinct pathways activated by c-MYC during apoptosis induction and transformation is crucial to the design of therapeutic strategies aimed at selectively reactivating the apoptotic potential of c-MYC in cancer cells. We recently demonstrated that apoptosis induction in primary human cells strictly requires that c-MYC bind and inactivate the transcription factor MIZ-1. This presumably blocked the ability of MIZ-1 to activate the transcription of an unidentified pro-survival gene. Here we report that MIZ-1 activates the transcription of BCL2. More importantly, inhibition of the MIZ-1/BCL2 signal is an essential event during the apoptotic response. Furthermore, targeting BCL2 with short hairpin RNA or small molecule inhibitors restores the apoptotic potential of a c-MYC mutant that is defective for MIZ-1 inhibition. These observations suggest that repression of BCL2 transcription is the single essential consequence of targeting the MIZ-1 pathway during apoptosis induction. These data define a genetic pathway that helps to explain historical observations documenting cooperation between c-MYC and BCL2 overexpression in human cancer.

Received for publication September 26, 2006. Revision received November 1, 2006.

* This work was supported in part by Grant CA090465 from the National Institutes of Health (to S. B. M.) and by funds from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department 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.


Formula

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

1 Supported by National Institutes of Health Grant T32-CA09171.

2 To whom correspondence should be addressed: Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., Philadelphia, PA 19107. Tel.: 215-955-9064; E-mail: Steven.McMahon{at}jci.tju.edu.

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