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The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exhibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain- and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered.  相似文献   

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混合连锁白血病因子4 (mixed lineage leukemia 4, MLL4)是组蛋白H3第4位赖氨酸(H3K4)一种特异的甲基化转移酶,也是COMPASS/Set1-like蛋白复合物中重要成员之一。MLL4蛋白本身及其介导的H3K4甲基化修饰,均能引起染色质结构和功能的改变,调控基因转录与表达。随着近年对MLL4蛋白研究的深入,MLL4基因、MLL4蛋白、蛋白复合物在各组织器官的发育、肿瘤疾病等生理与病理生理过程中的作用逐渐被揭示。本文对MLL4基因、MLL4蛋白特征、生物学功能及其对疾病的影响等方面的研究进展进行综述,以期进一步理解组蛋白甲基化转移酶对基因表达调控的影响及其非酶学依赖的功能,为相关疾病预防和诊治提供新的思路。  相似文献   

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组蛋白甲基转移酶MLL1因其基因易位重排所引起的混合系白血病(mixed lineage leukemia)而得名。MLL1蛋白在基因调控、细胞增殖、生长分化等正常生理功能中发挥着重要作用,染色体易位重排所产生的MLL1融合蛋白则与急性白血病的发生发展密切相关。目前人们对MLL1蛋白的结构和功能研究取得了很大的进展,为以MLL1和其相互作用蛋白为靶点的新型MLL白血病药物设计奠定了坚实的基础。  相似文献   

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WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein–protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1–WDR5 PPI. These inhibitors efficiently inhibited the histone methyltransferase activity in vitro. Especially, WL-15 was one of the most potent inhibitors, blocking the interaction of MLL1–WDR5 with IC50 value of 26.4 nM in competitive binding assay and inhibiting the catalytic activity of MLL1 complex with IC50 value of 5.4 μM. Docking model indicated that ester compounds suitably occupied the central cavity of WDR5 protein and recapitulated the interactions of WDR5-0103 and the hydrophobic groups and key amino greatly increased the activity in blocking MLL1–WDR5 PPI.  相似文献   

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目的:探讨传统教学法(LBL)、微课教学法(MLL)、MLL与LBL相结合的教学法在基层医生胸外科临床培训过程中的教学效果。方法:将唐都医院第10期陕西省基层医生培训班的120名基层医生随机分为LBL教学组、MLL教学组、MLL与LBL相结合教学组三组,每组各40人。在培训结束时,采用理论知识考试及实践技能考查进行量化考核,评估三种不同教学方法的教学效果。同时采用问卷调查,评价对三种教学方法的认同度。结果:LBL组学生的理论知识测试成绩较好(P0.005),而实践技能考查成绩较差(P0.001);MLL组学生的理论知识测试成绩较差(P0.005),而实践技能考查成绩较好(P0.001);MLL与LBL相结合组学生在理论知识测试和实践技能考查成绩两方面都较好(P0.0001)。问卷调查结果显示,MLL教学法、MLL与LBL相结合的教学法都得到了较好的认同度(P0.05)。结论:MLL与LBL相结合的教学法不仅提高了基层医师对理论知识的记忆,而且能够使其将所学知识更灵活运用到实践操作中,综合素质也得到很大的提高。  相似文献   

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在组蛋白H3K4甲基转移酶MLL3的催化结构域(MLL3SET)中定点引入非天然氨基酸N-炔丙基赖氨酸(N-propargyl-lysine,PrK),表达、纯化该突变蛋白(MLL3SET*),并评估突变蛋白的酶活,为后续进一步利用单分子荧光共振能量转移技术(smFRET)表征MLL3的作用机制奠定基础.将MLL3SE...  相似文献   

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The mixed lineage leukemia-1 (MLL1) core complex predominantly catalyzes mono- and dimethylation of histone H3 at lysine 4 (H3K4) and is frequently altered in aggressive acute leukemias. The molecular mechanisms that account for conversion of mono- to dimethyl H3K4 (H3K4me1,2) are not well understood. In this investigation, we report that the suppressor of variegation, enhancer of zeste, trithorax (SET) domains from human MLL1 and Drosophila Trithorax undergo robust intramolecular automethylation reactions at an evolutionarily conserved cysteine residue in the active site, which is inhibited by unmodified histone H3. The location of the automethylation in the SET-I subdomain indicates that the MLL1 SET domain possesses significantly more conformational plasticity in solution than suggested by its crystal structure. We also report that MLL1 methylates Ash2L in the absence of histone H3, but only when assembled within a complex with WDR5 and RbBP5, suggesting a restraint for the architectural arrangement of subunits within the complex. Using MLL1 and Ash2L automethylation reactions as probes for histone binding, we observed that both automethylation reactions are significantly inhibited by stoichiometric amounts of unmethylated histone H3, but not by histones previously mono-, di-, or trimethylated at H3K4. These results suggest that the H3K4me1 intermediate does not significantly bind to the MLL1 SET domain during the dimethylation reaction. Consistent with this hypothesis, we demonstrate that the MLL1 core complex assembled with a catalytically inactive SET domain variant preferentially catalyzes H3K4 dimethylation using the H3K4me1 substrate. Taken together, these results are consistent with a “two-active site” model for multiple H3K4 methylation by the MLL1 core complex.  相似文献   

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