[摘要] RUNX1又称为AML1，是人类白血病中染色体易位最常见的靶位点。RUNX1是十分重要的转录因子，在多种造血细胞系中广泛表达，在造血细胞的分化中起着关键作用，亦可调节造血相关基因的表达。RUNX1基因异常表达和突变常与人类白血病的发生相关。许多研究表明RUNX1是造血细胞生成过程中重要的调节因子，RUNX1蛋白可接受多种翻译后修饰，包括磷酸化、乙酰化等，其活性可受这些翻译后修饰的影响，从而调节造血细胞的分化、凋亡及自我更新。通过对RUNX1基因的研究旨在为白血病的进一步治疗提供新的靶点。
[关键词] RUNX1； 急性白血病； 翻译后修饰； 染色体易位
[] B[文章编号] 1005-0515（2012）-02-002-02
The relationship between RUNX1 and leukemia
LU ShanliangMA Xudong
(Department of Hematology Zhangzhou Affiliated Hospital of Fujian Medical UniversityFujian Zhangzhou363000 China)
[Abstract] RUNX1,called AML1,is one of the most frequent targets of translocations associated with human leukemias,which encodes a transcription factor that is widely expressed in multiple hematopoietic lineages and that plays a pivotal role in hematopoietic differentiation.Improper expression and mutations in Runx1 are frequently implicated in human leukemia.It also regulates the expression of a variety of hematopoietic genes.Numerous studies he shown that RUNX1 is a critical regulator of hematopoietic development.The RUNX1 can be modulated by various types of posttranslational modification,including phosphorylation,acetylation and so on. RUNX1 post-transcriptional modification can affect its role in influencing differentiation and self-renewal of hematopoietic cells.The goal of the studies of the RUNX1 gene is to develop new targets for leukemia.
[Key words] RUNX1 gene； human leukaemia； post-transcriptional； chromosomal translocation
RUNX蛋白家族是一类具有高度保守蛋白序列的转录因子家族，调节着参与细胞分化和细胞增殖的基因的表达。RNUX蛋白家族，在哺乳动物中包括3个成员，RUNX1、RUNX2和RUNX3，其中RUNX1亦称作急性髓系白血病1(acutemyeloid leukemia1,AML1)，是造血过程中关键的调节因子，是人类白血病中多种染色体易位的常见靶位点；在果蝇中包括两种同源物。RUNX在正常及恶性造血、血管形成、胸腺T细胞发育及细胞分化等多方面具有十分重要的作用，还参与与自身免疫性疾病如系统性红斑狼疮、类风湿性关节炎及牛皮癣的易感性相关[3]。
1 RUNX1结构和功能 RUNX1基因位于染色体21q22.3，由12个外显子组成，全长超过260 kb。RUNX1基因编码异二聚体转录因子的α亚基，能够与从胞浆进入胞核的核结合因子β亚基形成异二聚体-AMLI/CBFβ，已知该二聚体是维持正常造血的关键转录调控复合物。α亚基是1个核蛋白，具有3大功能结构域，其一为靠近N端的DNA结合区，由128个氨基酸组成，具有高度保守性，因这一区域与果蝇的Runt蛋白的一个区域同源而得名，称为Runt同源结构域(runt homology domain,RHD)。RHD介导Runx蛋白质α与β亚基的异二聚体化(CBFβ不能直接同DNA结合，但CBFβ能与CBFα形成异源二聚体并能稳定CBFα与DNA的结合[4])以及Runx蛋白质与其保守的DNA靶序列PyG-PyGGT(Py为嘧啶碱基)的结合。这种结合导致靶基因的激活或抑制。RUNX1的另一个功能区为靠近C端的反式激活结构域(transactivation domain,TD)。该区域可与转录共激活因子结合上调靶基因转录。RUNX1的最后一个功能区为转录抑制结构域(repressiondomain,RD)，该结构域分为3个不同的区域，分别命名为RD1、RD2及RD3，它们可介导RUNX1的抑制功能，其中RD1位于RHD的C端，该区域可招募共抑制因子SIN3A及EAR-2抑制靶基因的转录；RD2位于TD的C端，是转录抑制和T源于：毕业论文致谢词范文www.808so.com
细胞在胸腺组织器官的成熟过程中CD4沉默所必需的。研究发现，组蛋白转移酶SUV39H1及组蛋白去乙酰基转移酶1、3可与该区域相互结合，发挥转录抑制及基因沉默作用[5]；RD3位于RUNX1蛋白的C末端，该区域内包含VWRPY序列，它是转录共抑制因子TLE家族的识别序列，该转录抑制因子可与RUNX1蛋白发生相互作用抑制靶基因的转录。
RUNX1基因由于不同的转录后拼接可产生至少3不同的蛋白质: RUNX1a、RUNX1b、RUNX1c，分别为250个氨基酸、453个氨基酸和480个氨基酸。由于RUNX1b及RUNX1c均含有N端的RHD及C端的TD区,故RUNX1b及RUNX1c的功能大致相似。由于RUNX1a只保留了RHD，缺少TD区，研究表明RUNX1a和RUNX1b在调控粒细胞分化过程中呈相互拮抗作用，RUNX1a能显性抑制由RUNX1b引起的转录激活，并且RUNX1a比RUNX1b 与DNA结合有更高的亲和力。另外RUNX1a在大多数髓细胞性白血病患者细胞中有增多表达，这说明RUNX1a在白血病的发生机制中可能占一个重要地位，它可能显性抑制RUNX1b的功能而导致细胞的分化[6]。
在个体器官发育过程中，RUNX1在造血干细胞、主动脉一性腺一中肾区域的内皮细胞、软骨形成中心、嗅觉和味觉粘膜以及神经节细胞中均有较高的表达，而在器官形成后主要在造血细胞中表达。Runx1可调节大量造血相关基因的表达，通过转录调控，促进造血干细胞的发育和分化。在正常及恶性造血等方面起着重要的作用。
源于：论文网www.808so.com
参考文献
van Wijnen AJ,Stein GS,Gergen JP et al.Nomenclature for Runt-related(RUNX)proteins[J].Oncogene,2004,23(24):4209-4210.
Durst KL,Hiebert SW.Role of RUNX family members in transcriptional repression and gene silencing[J].Oncogene,2004,23(24):4220-4224.
[3] Prokunina L,Castillejo-Lopez C,Oberg F et al.A regulatory polymorphi in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans[J].Nat.Genet,2002,32(4):666-669.
[4] Wang S,Wang Q,Crute BE,Melnikova IN,Keller SR,Speck NA.Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor[J].Mol Cell Biol,1993,13:3324-3339.
[5] Reed-Inderbitzin E,Moreno-Miralles I,Vanden-Eynden SK.RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription[J].Oncogene,2006,25(42):5777-5786.
[6] 李先根,邬韦秀,周柱等.AMLI基因分子生物学研究进展[J].国外医学遗传学分册,1997,20(2):80-82.
[7] WangL,HuangG,ZhaoX etal.Post-translational modifications of Runx1 regulate its activity in the cell[J].Blood Cells Mol Dis,2009,43(1):30-34.
[8] Tanaka T,Kurokawa M,Ueki K et al.The extracellular signal-regulated kinase pathway phosphorylates AML1,an acute myeloid leukemia gene product,and potentially regulates its transactivation ability[J].Mol Cell Biol,1996,16(7):3967-3979.
[9] I mai Y,Kurokawa M,Yamaguchi Y et al.The corepressor mSin3A regulates phosphorylation-induced activation,intranuclear location,and stability of AML1[J].Mol Cell Biol,2004,24(3):1033-1043.
[10] Ichikawa M,Asai T,Saito T et al.AML-1 is required for megakaryocytic maturation and lymphocytic differentiation,but not for maintenance of hematopoietic stem cells in adult hematopoiesis[J].Nat Med,2004,10(3):299-304.
[11] Rebel VI,Kung AL,Tanner EA et al.Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal[J].ProcNatlAcad SciUS A,2002,99(23):14789-14794.
[12]Yang XJ,Ullah M.MOZ and MORF,two large MYSTic HATs in normal and cancer stem cells[J].Oncogene,2007,26(37):5408-5419.
[13] Kitabayashi I,Aikawa Y,Nguyen LA et al.Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein[J].EMBO J,2001,20(24):7184-7196.
[14] Nguyen LA,Pandolfi PP,Aikawa Y et al.Physical and functional link of the leukemia-associated factors AML1 and PML[J].Blood,2005,105(1):292-300.
[15] Chakraborty S,Sinha KK,Senyuk V et al.SUV39H1 interacts with AML1 and abrogates源于：论文库www.808so.com
AML1 transactivity.AML1 is methylated in vivo[J].Oncogene,2003,22(34):5229-5237.
[16] Zhao X,Jankovic V,Gural A et al.Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity[J].Genes Dev,2008,22(5):640-653.
[17] Huang G,Shigesada K,Ito K et al.Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation[J].EMBO J,2001,20(4):723-733.
[18] Shang Y,Zhao X,Xu X et al.CHIP functions an E3 ubiquitin ligase of Runx [J].Biochem Biophys Res Commun,2009,386(1):242- 246.
[19] Yamagata T,Maki K,Mitani K.Runx1/AML1 in normal and abnormal hematopoiesis[J].Int J Hematol,2005,82(1):1-8.
[20] KurokawaM,HiraiH.Role of AML1/Runx1 in the pathogenesis of hematological m alignancies[J].Cancer SCI,2003,94(10):841- 846.
[21] Roulston D,Espinosa R 3rd,Nucifora G.CBFA2(AML1)translocations with novel partner chromosomes in myeloideukemias:association with prior therapy[J].Blood,1998,92(8):2879-2885.
[22] 戴海萍,薛永权.恶性血液病中涉及AMLI的染色体易位[J].国际输血及血液学杂志,2006,29(4):306-309.
[23] Li D,Sinha KK,Hay MA et al.RUNX1-RUNX1 homodimerization modulates RUNX1 activity and function[J].J Biol Chem ,2007,282(18):13542-13551.
RUNX1与白血病
更新时间：2024-01-28
作者：用户投稿
本站原创
本站原创
点赞:24255 浏览:115254