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Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin To Regulate Hox Gene Expression

机译:白血病原癌蛋白MLL与Menin形成SET1样组蛋白甲基转移酶复合物,以调节Hox基因表达

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摘要

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 1 (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 MLL 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.
机译:MLL(用于混合谱系白血病)是一种原癌基因,可在多种人类白血病中发生突变。其产品是果蝇果蝇的同系物,显示出固有的组蛋白甲基转移酶活性,并在遗传上具有维持胚胎Hox基因表达的功能。在这里,我们报告了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(包括另一个Trx-G组蛋白Ash2的同源物)共享的一组蛋白质有关。此处鉴定的新型MLL复合物的另外两个成员是宿主细胞因子1(HCF-1),转录共调节因子和相关的HCF-2,两者均与MLLN(p300)亚基中的保守结合基序特异性相互作用。 MLL并提供了调节其拮抗转录特性的潜在机制。 Menin,MEN1肿瘤抑制基因的产物,也是1-MDa MLL复合物的组成部分。 Menin表达的废除表型反映了MLL的丧失,并揭示了Menin在维持Hox基因表达中的关键作用。 MLL的致癌突变体形式保留与menin相互作用的能力,但不与其他已鉴定的复杂成分相互作用。这些研究将menin肿瘤抑制蛋白与MLL组蛋白甲基转移酶机制相关联,对Hox基因在发育和白血病发病中的表达具有影响。

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