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J. Biol. Chem., Vol. 279, Issue 11, 10685-10691, March 12, 2004

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Menin Induces Apoptosis in Murine Embryonic Fibroblasts^*

Robert W. Schnepp, Hua Mao, Stephen M. Sykes, Wei-Xing Zong, Albert Silva, Ping La, and Xianxin Hua

From the Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160

Multiple endocrine neoplasia type I (MEN1) is a hereditary tumor syndrome characterized by multiple endocrine and occasionally non-endocrine tumors. The tumor suppressor gene Men1, which is frequently mutated in MEN1 patients, encodes the nuclear protein menin. Although many tumor suppressor genes are involved in the regulation of apoptosis, it is unclear whether menin facilitates apoptosis. Here we show that ectopic overexpression of menin via adenoviruses induces apoptosis in murine embryonic fibroblasts. The induction of apoptosis depends on Bax and Bak, two proapoptotic proteins. Moreover, loss of menin expression compromises apoptosis induced by UV irradiation and tumor necrosis factor- (TNF-), whereas complementation of menin-null cells with menin restores sensitivity to UV- and TNF--induced apoptosis. Interestingly, loss of menin reduces the expression of procaspase 8, a critical protease that is essential for apoptosis induced by death-related receptors, whereas complementation of the menin-null cells up-regulates the expression of procaspase 8. Furthermore, complementation of menin-null cells with menin increases the activation of caspase 8 in response to TNF- treatment. These results suggest a proapoptotic function for menin that may be important in suppressing the development of MEN1.

Received for publication, July 24, 2003 , and in revised form, December 18, 2003.

^* This work was supported in part by Howard Temin Award K01CA78592 (to X. H.), Burroughs Wellcome Career Award 1676 (to X. H.), an award from the Rita Alan Foundation (to X. H.), and American Cancer Society Grant RSG-03-055-01-LIB. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 215-746-5565; Fax: 215-746-5525; E-mail: huax{at}mail.med.upenn.edu.

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