Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus
Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus
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DOI：
10.1016/s1097-2765(04)00081-4
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发表时间：
2004-02-27
期刊：
影响因子：
16
通讯作者：
Meyerson, M
中科院分区：
文献类型：
--
作者：
Hughes, CM;Rozenblatt-Rosen, O;Meyerson, M
menin肿瘤抑制蛋白是家族性多发性内分泌瘤1型中MEN1基因突变的产物，其细胞功能尚未确定。我们现在表明，menin是与组蛋白甲基转移酶复合物含有两个三胸家族蛋白，MLL2和Ash2L，和其他同源的酵母Set1大会。这种脑膜炎相关复合物甲基化赖氨酸4上的组蛋白H3。肿瘤衍生的menin突变体的一个子集缺乏相关的组蛋白甲基转移酶活性。此外，menin与RNA聚合酶II相关，RNA聚合酶II的大亚基羧基末端结构域在Ser5上磷酸化。Men1基因敲除的胚胎和细胞显示同源盒基因Hoxc6和Hoxc8的表达降低。染色质免疫沉淀实验表明，menin是绑定到Hoxc8位点。这些结果表明，menin通过共价组蛋白修饰激活分化调节基因的转录，并且这种活性与MEN1的肿瘤抑制有关。
The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1.