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J. Biol. Chem., Vol. 282, Issue 43, 31332-31340, October 26, 2007

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Menin-mediated Caspase 8 Expression in Suppressing Multiple Endocrine Neoplasia Type 1^*

Ping La, Yuqing Yang, Satyajit K. Karnik, Albert C. Silva, Robert W. Schnepp, Seung K. Kim, and Xianxin Hua¹

From the Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160 and the Departments of Developmental Biology and Medicine, Stanford University, Stanford, California 94305-5329

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome linked to mutation of the MEN1 gene, which encodes a tumor suppressor, menin. We previously reported that menin up-regulates the caspase 8 expression and promotes TNF--induced apoptosis. However, it remains unclear how menin up-regulates caspase 8 expression and whether menin-mediated caspase 8 expression plays a role in repressing MEN1 development. Here we show that menin binds the 5'-untranslated region (5'-UTR) of the Caspase 8 locus in vivo and activates transcription of a reporter gene through the 5'-UTR. Menin directly binds the 5'-UTR in a sequence-independent manner in vitro. Moreover, Men1 ablation in cells reduces acetylation of histones H3 and H4 at the 5'-UTR of the caspase 8 locus bound by menin in vivo. Notably, the MEN1-derived menin point mutants lose their ability to bind the caspase 8 locus and fail to induce caspase 8 expression and TNF--mediated apoptosis. Consistent with these observations, the expression level of caspase 8 is markedly reduced in insulinomas from Men1^+/– mice. Together, our results indicate that menin enhances the caspase 8 expression by binding the caspase 8 locus, and suggest that menin suppresses MEN1 tumorigenesis, at least in part, by up-regulating caspase 8 expression.

Received for publication, October 10, 2006 , and in revised form, August 29, 2007.

^* This work was supported in part by National Institutes of Health (NIH) Grants R01 CA113962 and R01 CA100912 (to X. H.). Work in the Kim laboratory was supported by grants from NIH, the Verto Institute, and the Stephen and Caroline Kaufer Fund for Neuroendocrine Tumor 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.

¹ 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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