Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors
Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors
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DOI：
10.1073/pnas.0408836102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Hess, JL
中科院分区：
文献类型：
--
作者：
Milne, TA;Hughes, CM;Hess, JL
MEN1基因的突变与1型多发性内分泌肿瘤综合征（MEN1）相关，其特征为甲状旁腺增生以及垂体和胰岛肿瘤。MEN1作为肿瘤抑制因子的作用机制尚不清楚。我们最近发现，MEN1蛋白产物——menin，在一个包含Ash2、Rbbp5和WDR5的组蛋白甲基转移酶复合物中与混合谱系白血病（MLL）家族蛋白相互作用。在此，我们表明menin直接调节细胞周期蛋白依赖性激酶抑制剂p27（Kip1）和p18（Ink4c）的表达。Menin通过一种涉及将MLL募集到p27（Kip1）和p18（Ink4c）启动子及编码区的机制激活转录。MLL或menin功能缺失会导致p27（Kip1）和p18（Ink4c）表达下调以及细胞生长失调。这些发现表明，menin和MLL之间的协同相互作用对细胞周期蛋白依赖性激酶抑制剂转录的调节在menin作为肿瘤抑制因子的活性中起核心作用。
Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MILL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27(Kip1) and p18(Ink4c). Menin activates transcription by means of a mechanism involving recruitment of MILL to the p27(Kip1) and p18(Ink4c) promoters and coding regions. Loss of function of either MILL or menin results in down-regulation of p27(KiP1) and p18(Ink4c) expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MILL plays a central role in menin's activity as a tumor suppressor.