Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression
Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression
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DOI：
10.1128/mcb.24.13.5639-5649.2004
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发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Yokoyama, A;Wang, Z;Cleary, ML
MLL（混合谱系白血病）是一种在多种人类白血病中发生突变的原癌基因。其产物是黑腹果蝇的同源物，具有内在的组蛋白甲基转移酶活性，并具有维持胚胎Hox基因表达的遗传功能。在这里，我们报道了MLL的生化纯化，并证明它与酵母和人类SET1组蛋白甲基转移酶复合物共享的一系列蛋白质相关，包括另一个Trx-G组蛋白Ash2的同源物。本文鉴定的新型MLL复合体的另外两个成员是宿主细胞因子I (HCF-1)，一种转录共调节因子，以及相关的HCF-2，它们都与MILL的MLLN （p300）亚基中的一个保守结合基序特异性相互作用，并提供了调节其拮抗转录特性的潜在机制。Menin是MEN1肿瘤抑制基因的产物，也是1-MDa MLL复合物的一个组成部分。menin表达的缺失反映了MLL的缺失，并揭示了menin在维持Hox基因表达中的关键作用。致癌突变形式的MLL保留了与menin相互作用的能力，但不与其他已确定的复杂成分相互作用。这些研究将脑膜蛋白肿瘤抑制蛋白与MLL组蛋白甲基转移酶机制联系起来，对Hox基因在发育和白血病发病中的表达具有重要意义。
MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. Here we report the biochemical purification of MLL and demonstrate that it associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including a homolog of Ash2, another Trx-G group protein. Two other members of the novel MLL complex identified here are host cell factor I (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLLN (p300) subunit of MILL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.