Functional interaction between tumor suppressor menin and activator of S-phase kinase
Functional interaction between tumor suppressor menin and activator of S-phase kinase
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DOI：
10.1158/0008-5472.can-04-0724
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Hua, XX
中科院分区：
文献类型：
--
作者：
Schnepp, RW;Hou, ZY;Hua, XX
多发性内分泌瘤I型（MEN 1）是一种遗传性肿瘤综合征，其特征是肿瘤发生于多个内分泌器官。MEN 1患者中突变的基因Men 1编码肿瘤抑制因子menin。menin的过度表达导致Rastransformed细胞的抑制。然而，目前还不清楚menin是否对抑制细胞增殖至关重要，如果是，它如何抑制细胞增殖。在这里，我们表明，有针对性的破坏Men 1基因导致增强细胞增殖，而补充menin空细胞与menin减少细胞增殖。此外，menin与S期激酶（ASK）的激活剂相互作用，这是Cdc 7/ASK激酶复合物的一种组分，对细胞增殖至关重要，但在体外激酶测定中似乎不会改变Cdc 7激酶活性。我们确定的COOH端的menin介导的域与ASK的具体相互作用。值得注意的是，野生型menin完全抑制ASK诱导的细胞增殖，虽然它不明显影响ASK感染细胞的稳态细胞周期谱。有趣的是，不与ASK相互作用的疾病相关的COOH末端menin突变体完全不能抑制ASK诱导的细胞增殖。总之，这些发现证明了menin和ASK在细胞增殖调节中的功能联系。
Multiple endocrine neoplasia type I (MEN1), a hereditary tumor syndrome, is characterized by the development of tumors in multiple endocrine organs. The gene mutated in MEN1 patients, Men1, encodes a tumor suppressor, menin. Overexpression of menin leads to inhibition of Rastransformed cells. However, it is unclear whether menin is essential for repression of cell proliferation, and if it is, how it inhibits cell proliferation. Here, we show that targeted disruption of the Men1 gene leads to enhanced cell proliferation, whereas complementation of menin-null cells with menin reduces cell proliferation. Moreover, menin interacts with activator of S-phase kinase (ASK), a component of the Cdc7/ASK kinase complex that is crucial for cell proliferation, but does not appear to alter Cdc7 kinase activity in in vitro kinase assays. We identify the COOH terminus of menin as the domain that mediates the specific interaction with ASK. Notably, wild-type menin completely represses ASK-induced cell proliferation, although it does not obviously affect the steady-state cell cycle profile of ASK-infected cells. Interestingly, disease-related COOH-terminal menin mutants that do not interact with ASK completely fail to repress ASK-induced cell proliferation. Together, these findings demonstrate a functional link between menin and ASK in the regulation of cell proliferation.