HDAC1与乙酰化HDAC1对辅阻遏物复合体活性及机体造血作用的影响

发布时间：2018-05-19 15:49

本文选题：HDAC1 + HDAC2　；参考：《吉林大学》2009年博士论文

【摘要】：组蛋白去乙酰化酶(HDACs)在真核生物基因表达调控中发挥着重要的作用,抑制HDACs的活性会引起多种癌细胞的生长抑制、细胞分化和凋亡。组蛋白去乙酰化酶1(HDAC1)和2(HDAC2)同属Ⅰ类组蛋白去乙酰化酶,而且高度同源,通常同时存在于相同的辅阻遏物复合体中。之前我们发现HDAC1参与糖(肾上腺)皮质激素受体(GR)介导的转录调控,并且HDAC1能够被组蛋白乙酰基转移酶p300乙酰化而失去活性.在本研究中发现HDAC2也同样参与GR介导的转录活性调控,不过与HDAC1不同的是HDAC2不能被p300乙酰化,尽管HDAC1中6个被乙酰化的赖氨酸残基有5个也存在于HDAC2中。进一步研究表明,通过形成异二聚体,乙酰化的HDAC1能够抑制HDAC2的活性,同样失去活性的HDAC2也可以抑制HDAC1的活性,从而揭示了包含HDAC1/2的辅阻遏物复合体协同调控的新机制。组蛋白去乙酰化酶在血细胞生成和白血病生成中发挥着重要的作用。已显示HDAC1能与许多机体造血转录因子相结合,如GATA1,TAL1,EKLF,AML1,ETO2等并影响它们的活性。研究发现在被诱导分化的小鼠红细胞白血病细胞(MEL)中与GATA1相结合的HDAC1被乙酰化并失去活性,在血细胞中过表达HDAC1能够促进血细胞的增殖并抑制分化,反之在血细胞中敲除HDAC1或HDAC2能抑制血红细胞的增殖并促进分化,而且HDAC1能够负调控GATA1的转录活性,GATA1与NuRD/MeCP1复合体之间的动态调控,决定血红细胞分化的发生和发展,并为探索白血病的致病机理奠定了理论基础。
[Abstract]:Histone deacetylase (HDACs) plays an important role in the regulation of eukaryotic gene expression. Inhibition of HDACs activity can cause the growth inhibition, cell differentiation and apoptosis of various cancer cells. Histone deacetylase 1 (HDAC1) and 2 (HDAC2) belong to class I histone deacetylase, and are highly homologous, usually at the same time. In the same repressor complex, we found that HDAC1 was involved in the transcriptional regulation mediated by glucocorticoid receptor (GR), and HDAC1 could be deactivated by histone acetyltransferase P300 acetylation. In this study, it was found that HDAC2 was also involved in GR mediated transcriptional activity regulation, but unlike HDAC1, HDAC2 did not. It can be acetylated by P300, although 5 of the 6 acetylated lysine residues in HDAC1 also exist in HDAC2. Further studies have shown that by forming a hetero two polymer, acetylation of HDAC1 can inhibit the activity of HDAC2, and the activity of HDAC2 can also inhibit the activity of HDAC1, thus revealing the co repressor complex containing HDAC1/2 A new mechanism for the same regulation. Histone deacetylase plays an important role in blood cell formation and leukemic formation. It has been shown that HDAC1 can be combined with many human transcription factors, such as GATA1, TAL1, EKLF, AML1, ETO2 and so on. It has been found in induced differentiated mouse erythroleukemia cells (MEL). The HDAC1, which is combined with GATA1, is acetylation and inactive. Over expression of HDAC1 in blood cells can promote the proliferation of blood cells and inhibit differentiation. On the contrary, the knockout of HDAC1 or HDAC2 in blood cells can inhibit the proliferation of blood red cells and promote differentiation, and HDAC1 can negatively regulate the transcriptional activity of GATA1, between GATA1 and NuRD/MeCP1 complex. Dynamic regulation determines the occurrence and development of erythrocyte differentiation, and lays a theoretical foundation for exploring the pathogenesis of leukemia.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R346;R733.7

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