Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway
Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway
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DOI：
10.1128/mcb.24.15.6569-6580.2004
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发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Tsukada, T
中科院分区：
文献类型：
--
作者：
Yaguchi, H;Ohkura, N;Tsukada, T
MEN 1是一种肿瘤抑制基因，负责多发性内分泌瘤1型（MEN 1），编码一种610个氨基酸的蛋白质，称为menin。虽然在MEN 1患者中鉴定的大多数生殖系突变是导致menin蛋白截短的移码和无义突变，但已鉴定出各种错义突变，其对menin活性的影响尚不清楚。在这项研究中，我们分析了一系列具有单个氨基酸改变的menin蛋白，发现与野生型和良性多态性menin蛋白水平相比，所有测试的MEN 1引起的错义突变导致受影响蛋白的水平大大降低。我们在这里证明，突变蛋白的水平降低是由于通过泛素-蛋白酶体途径的快速降解。此外，突变体，但不是野生型menin，相互作用的分子伴侣Hsp 70和与Hsp 70相关的泛素连接酶CHIP，和CHIP的过表达促进泛素化的menin突变体在体内。这些发现表明，MEN 1引起的错义突变导致menin功能丧失，这是由于蛋白水解降解增强，这可能是家族性癌症中肿瘤抑制基因产物失活的常见机制。
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.