Cattaneo Francesca, Nucifora Giuseppina
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
J Cell Biochem. 2008 Oct 1;105(2):344-52. doi: 10.1002/jcb.21869.
EVI1 is an oncoprotein inappropriately expressed in acute myeloid leukemia and myelodysplastic syndrome cells. In vitro studies indicate that diverse biological properties can be attributed to this protein. Its role in leukemogenesis is still unclear but it is thought that overall EVI1 can act mostly as a transcription repressor through its interaction with a subset of histone deacetylases. Studies with histone deacetylase inhibitors have however indicated that EVI1-mediated repression can be only partially rescued by deacetylase inhibitor drugs, suggesting that additional chromosomal modifications might occur to induce gene repression by EVI1. To investigate whether histone methylation contributes to the repressive potential of EVI1, we examined a potential association between EVI1, the histone methyltransferase (HMT) SUV39H1, and methyltransferase activity in vitro. We find that EVI1 directly interacts with SUV39H1 and that the proteins form an active complex with methyltransferase activity in vitro. Our data indicate that SUV39H1 enhances the transcription repressive potential of EVI1 in vivo. We suggest that EVI1 affects promoters' activity in two different pathways, by association with histone deacetylases and by recruiting chromatin-modifying enzymes to impose a heterochromatin-like structure establishing a lasting transcription repression.
EVI1是一种在急性髓系白血病和骨髓增生异常综合征细胞中异常表达的癌蛋白。体外研究表明，这种蛋白具有多种生物学特性。其在白血病发生中的作用仍不清楚，但一般认为EVI1主要通过与一部分组蛋白脱乙酰酶相互作用而作为转录抑制因子发挥作用。然而，对组蛋白脱乙酰酶抑制剂的研究表明，脱乙酰酶抑制药物只能部分挽救EVI1介导的抑制作用，这表明可能还会发生其他染色体修饰以诱导EVI1介导的基因抑制。为了研究组蛋白甲基化是否有助于EVI1的抑制潜能，我们在体外检测了EVI1、组蛋白甲基转移酶（HMT）SUV39H1和甲基转移酶活性之间的潜在关联。我们发现EVI1直接与SUV39H1相互作用，并且这些蛋白在体外形成了具有甲基转移酶活性的活性复合物。我们的数据表明，SUV39H1在体内增强了EVI1的转录抑制潜能。我们认为，EVI1通过与组蛋白脱乙酰酶结合以及招募染色质修饰酶以形成类似异染色质的结构来建立持久的转录抑制，从而通过两种不同途径影响启动子的活性。
