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Molecular and Cellular Biology, August 2004, p. 6569-6580, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6569-6580.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Menin Missense Mutants Associated with Multiple Endocrine Neoplasia Type 1 Are Rapidly Degraded via the Ubiquitin-Proteasome Pathway

Hiroko Yaguchi,¹ Naganari Ohkura,^1* Maho Takahashi,¹ Yuko Nagamura,¹ Issay Kitabayashi,² and Toshihiko Tsukada¹

Tumor Endocrinology Project,¹ Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan²

Received 15 January 2004/ Returned for modification 20 February 2004/ Accepted 7 May 2004

MEN1 is a tumor suppressor gene that is responsible for multiple endocrine neoplasia type 1 (MEN1) and that encodes a 610-amino-acid protein, called menin. While the majority of germ line mutations identified in MEN1 patients are frameshift and nonsense mutations resulting in truncation of the menin protein, various missense mutations have been identified whose effects on menin activity are unclear. For this study, we analyzed a series of menin proteins with single amino acid alterations and found that all of the MEN1-causing missense mutations tested led to greatly diminished levels of the affected proteins in comparison with wild-type and benign polymorphic menin protein levels. We demonstrate here that the reduced levels of the mutant proteins are due to rapid degradation via the ubiquitin-proteasome pathway. Furthermore, the mutants, but not wild-type menin, interact both with the molecular chaperone Hsp70 and with the Hsp70-associated ubiquitin ligase CHIP, and the overexpression of CHIP promotes the ubiquitination of the menin mutants in vivo. These findings reveal that MEN1-causing missense mutations lead to a loss of function of menin due to enhanced proteolytic degradation, which may be a common mechanism for inactivating tumor suppressor gene products in familial cancer.

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* Corresponding author. Mailing address: Tumor Endocrinology Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511. Fax: 81-3-3542-8170. E-mail: nohkura{at}gan2.res.ncc.go.jp.

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Molecular and Cellular Biology, August 2004, p. 6569-6580, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6569-6580.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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