新基因MIP2的表达及心肌细胞保护作用研究
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摘要
WD-重复结构是由约40-60个氨基酸组成的保守蛋白质结构域,大多数含WD-重复结构的蛋白包含4-16个WD-重复结构域,他们构成了WD-重复蛋白超家族。该家族成员的核苷酸序列在真核生物不同物种间高度保守,表明其功能对生命活动的重要性。目前已发现的WD-重复蛋白家族成员多为调节因子,功能涉及信号转导、RNA合成和加工、染色体排列、细胞周期调控、细胞凋亡等多方面,其中最具代表性的成员为G蛋白。
MIP2是本室从经历短暂缺血-再灌注的大鼠心肌中发现的表达上调的新基因,命名为缺血预适应上调蛋白2(myocardial ischemic preconditioning upregulated protein 2, MIP2),其GenBank登录号为AY221751。本室前期应用生物信息学的同源性分析和RT-PCR技术克隆得到人的同源新基因MIP2,并利用生物信息学软件对其核酸和蛋白质的结构进行了初步的分析。其最大开放阅读框(open reading frame, ORF)为1497bp,编码498个氨基酸。其编码肽链的N-端含一CTLH结构域,C-端含5个WD40结构域,故为一典型的WD-重复蛋白。
在本研究中,我们首先采用生物信息学的多种软件对MIP2核酸和蛋白质的结构、一般生化特性以及生物学功能进行了多方位预测,发现MIP2是一个酸性蛋白,亲水性较弱,疏水性较强；存在信号肽序列的可能性为零,不可能被分泌到细胞外；存在蛋白激酶C磷酸化位点、酪蛋白激酶Ⅱ磷酸化位点、酪氨酸激酶磷酸化位点等多种磷酸化位点,推测MIP2基因的活化可能受磷酸化作用的调控。MIP2蛋白的二级结构中,主要以α-螺旋、不规则盘绕和延伸链为蛋白最大量的结构元件,β-折叠散布于整个蛋白质中；三维结构预测发现MIP2蛋白类似环状的螺旋推进器样结构,可提供十分稳定牢靠的蛋白质相互作用的平台,促进多蛋白复合物的形成。SAGE电子表达谱分析表明,MIP2基因在人的大多数正常组织及肿瘤组织中有表达,在心肌中表达较高。
虽然MIP2是从大鼠缺血预适应心肌中分离的上调基因,但目前对其表达模式仍不清楚。本研究首先采用大鼠心肌缺血预适应及缺血-再灌注模型,观察心肌中MIP2的mRNA及蛋白质表达模式。研究发现,MIP2的mRNA在单纯缺血预适应、缺血-再灌注、预适应加缺血-再灌注心肌中表达水平均显著升高,且预适应加缺血-再灌注心肌中表达升高幅度最明显；缺血心肌中MIP2的mRNA表达量高于非缺血心肌。心肌缺血及再灌注后,其MIP2蛋白表达水平也增高。采用H9c2心肌细胞氧化应激模型发现,在200μM H2O2处理下,MIP2的mRNA表达明显增加,于4h达高峰,然后逐渐降低,于24h仍处较高水平。在50-200μM H2O2浓度下,MIP2蛋白质表达水平随着H2O2浓度的增加而升高。为观察MIP2的亚细胞定位,我们将包含有人MIP2最大开放阅读框(ORF)的真核表达质粒导入大鼠心室肌H9c2细胞中,建立了稳定过表达MIP2的GFP-MIP2-H9c2单克隆细胞株。通过荧光显微镜观察到MIP2主要定位于胞浆,采用线粒体指示剂MitoTracker发现MIP2部分定位于线粒体。H2O2处理细胞后,其亚细胞定位未见明显改变。
为进一步研究MIP2对心肌细胞增殖的影响,我们利用过表达MIP2的H9c2心肌细胞株来观察MIP2对心肌细胞增殖的影响。实验发现,过表达MIP2能促进H9c2心肌细胞的增殖,该促增殖效应与细胞MIP2的表达水平呈量效关系,且MIP2能促进H9c2细胞从G0／G1期向S期的行进、缩短细胞周期。这说明MIP2是一个与细胞增殖有关的基因。同时,在去血清的条件下,过表达MIP2也能加快H9c2心肌细胞的生长。这提示在缺氧及其他损伤因素作用下,MIP2有可能对心肌细胞发挥保护作用。
为进一步探讨MIP2对心肌细胞损伤的可能保护作用及其机制,本研究采用H2O2导致H9c2心肌细胞损伤,采用过表达或表达抑制策略探讨MIP2对H2O2所致H9c2细胞氧化应激损伤的影响及其可能机制。结果发现,过表达MIP2能减轻H2O2引起的H9c2细胞损伤及凋亡,能抑制细胞色素C从线粒体中释放,抑制caspase-9和caspase-3活性,但对caspase-8活性无明显抑制作用；运用RNA干扰沉默MIP2基因后,该保护作用明显减弱。上述结果说明,MIP2是通过抑制线粒体凋亡通路而对心肌细胞氧化应激损伤发挥保护作用。
WD40 repeats are short motifs with-40 amino acids, often terminating in a Trp-Asp (W-D) dipeptide. WD-containing proteins have 4 to 16 repeating units, all of which are thought to form a circularised beta-propeller structure. The best characterized WD repeat protein is theβ-subunit of the G proteins, which contains seven WD40 repeats. The WD40 family of proteins comprises a large number of proteins and participates in a wide variety of cellular functions including signal transduction, transcription, RNA processing, and the cell cycle.
MIP2 is a novel gene cloned in our laboratory that is up-regulated in ischemic preconditioned rat heart and we named it myocardial ischemic preconditioning up-regulated protein 2 (GenBank accession number: AY221751). It has an open reading frame of 1497 bp, encoding a polypeptide of 498 amino acids with an N-terminal CTLH domain and 5 C-terminal WD40 repeats.
Using bioinformatics techniques it was found that MIP2 is an acidic protein with high hydrophobicity, but with no signal peptide. It contains four protein kinase C phophorylation sites, four N-glycosylation sites, seven casein kinaseⅡphosphorylation sites, indicating that the activation of MIP2 may be controlled by phosphorlation. Majority of its motifs are alpha helixs, extended strands and random coils in its secondary structure. Three-dimensional structure analysis showed that five WD-repeats of MIP2 form a propeller structure. SAGE (Several Analysis of Gene Expression) analysis revealed that MIP2 was ubiquitously expressed in normal human tissues and broad kinds of tumors, with a high expression in the heart.
We next observed the expression pattern of MIP2 in models of myocardial ischemia/reperfusion (I/R) and myocardial ischemic preconditioning (IP) in rats. The mRNA and protein expression levels were up-regulated after I/R, IP, IP+I/R and H2O2 exposure. A higher mRNA expression of the MIP2 was observed in ischemic myocardium than in non-ischemic myocardium. To observe the subcellular localization of MIP2, a pEGFP-MIP2 fusion vector was constructed. It was found that MIP2 was located mainly in the cytoplasm, with a part of MIP2 distributed on mitochondria.
It was also found that stable overexpression of MIP2 in rat cardiomyoblast cell line H9c2 resulted in an enhanced growth of the cells in a dose-dependant manner as measured by cell number. Overexpression of MIP2 resulted in a shorter cell cycle, as measured by flow cytometry. Collectively, these data suggested that MIP2 promoted the proliferation of H9c2 cells.
It was further found that oxidative stress induced by H2O2 led to concurrent increases in necrosis and apoptosis in cultured H9c2 rat cardiomyocytes. Overexpression of MIP2 decreased the cardiotoxicity induced by H2O2, which is associated with inhibition of the activation of caspase-9 and caspase-3, as well as inhibition of releasing of cytochrome C from mitochondrion to cytoplasm. MIP2 silencing increased oxidative stress-induced necrosis and apoptosis in H9C2 cells. These results indicated that MIP2 could protect cardiomyocytes against oxidative stress-induced injury.
MIP2是本室从经历短暂缺血-再灌注的大鼠心肌中发现的表达上调的新基因,命名为缺血预适应上调蛋白2(myocardial ischemic preconditioning upregulated protein 2, MIP2),其GenBank登录号为AY221751。本室前期应用生物信息学的同源性分析和RT-PCR技术克隆得到人的同源新基因MIP2,并利用生物信息学软件对其核酸和蛋白质的结构进行了初步的分析。其最大开放阅读框(open reading frame, ORF)为1497bp,编码498个氨基酸。其编码肽链的N-端含一CTLH结构域,C-端含5个WD40结构域,故为一典型的WD-重复蛋白。
在本研究中,我们首先采用生物信息学的多种软件对MIP2核酸和蛋白质的结构、一般生化特性以及生物学功能进行了多方位预测,发现MIP2是一个酸性蛋白,亲水性较弱,疏水性较强；存在信号肽序列的可能性为零,不可能被分泌到细胞外；存在蛋白激酶C磷酸化位点、酪蛋白激酶Ⅱ磷酸化位点、酪氨酸激酶磷酸化位点等多种磷酸化位点,推测MIP2基因的活化可能受磷酸化作用的调控。MIP2蛋白的二级结构中,主要以α-螺旋、不规则盘绕和延伸链为蛋白最大量的结构元件,β-折叠散布于整个蛋白质中；三维结构预测发现MIP2蛋白类似环状的螺旋推进器样结构,可提供十分稳定牢靠的蛋白质相互作用的平台,促进多蛋白复合物的形成。SAGE电子表达谱分析表明,MIP2基因在人的大多数正常组织及肿瘤组织中有表达,在心肌中表达较高。
虽然MIP2是从大鼠缺血预适应心肌中分离的上调基因,但目前对其表达模式仍不清楚。本研究首先采用大鼠心肌缺血预适应及缺血-再灌注模型,观察心肌中MIP2的mRNA及蛋白质表达模式。研究发现,MIP2的mRNA在单纯缺血预适应、缺血-再灌注、预适应加缺血-再灌注心肌中表达水平均显著升高,且预适应加缺血-再灌注心肌中表达升高幅度最明显；缺血心肌中MIP2的mRNA表达量高于非缺血心肌。心肌缺血及再灌注后,其MIP2蛋白表达水平也增高。采用H9c2心肌细胞氧化应激模型发现,在200μM H2O2处理下,MIP2的mRNA表达明显增加,于4h达高峰,然后逐渐降低,于24h仍处较高水平。在50-200μM H2O2浓度下,MIP2蛋白质表达水平随着H2O2浓度的增加而升高。为观察MIP2的亚细胞定位,我们将包含有人MIP2最大开放阅读框(ORF)的真核表达质粒导入大鼠心室肌H9c2细胞中,建立了稳定过表达MIP2的GFP-MIP2-H9c2单克隆细胞株。通过荧光显微镜观察到MIP2主要定位于胞浆,采用线粒体指示剂MitoTracker发现MIP2部分定位于线粒体。H2O2处理细胞后,其亚细胞定位未见明显改变。
为进一步研究MIP2对心肌细胞增殖的影响,我们利用过表达MIP2的H9c2心肌细胞株来观察MIP2对心肌细胞增殖的影响。实验发现,过表达MIP2能促进H9c2心肌细胞的增殖,该促增殖效应与细胞MIP2的表达水平呈量效关系,且MIP2能促进H9c2细胞从G0／G1期向S期的行进、缩短细胞周期。这说明MIP2是一个与细胞增殖有关的基因。同时,在去血清的条件下,过表达MIP2也能加快H9c2心肌细胞的生长。这提示在缺氧及其他损伤因素作用下,MIP2有可能对心肌细胞发挥保护作用。
为进一步探讨MIP2对心肌细胞损伤的可能保护作用及其机制,本研究采用H2O2导致H9c2心肌细胞损伤,采用过表达或表达抑制策略探讨MIP2对H2O2所致H9c2细胞氧化应激损伤的影响及其可能机制。结果发现,过表达MIP2能减轻H2O2引起的H9c2细胞损伤及凋亡,能抑制细胞色素C从线粒体中释放,抑制caspase-9和caspase-3活性,但对caspase-8活性无明显抑制作用；运用RNA干扰沉默MIP2基因后,该保护作用明显减弱。上述结果说明,MIP2是通过抑制线粒体凋亡通路而对心肌细胞氧化应激损伤发挥保护作用。
WD40 repeats are short motifs with-40 amino acids, often terminating in a Trp-Asp (W-D) dipeptide. WD-containing proteins have 4 to 16 repeating units, all of which are thought to form a circularised beta-propeller structure. The best characterized WD repeat protein is theβ-subunit of the G proteins, which contains seven WD40 repeats. The WD40 family of proteins comprises a large number of proteins and participates in a wide variety of cellular functions including signal transduction, transcription, RNA processing, and the cell cycle.
MIP2 is a novel gene cloned in our laboratory that is up-regulated in ischemic preconditioned rat heart and we named it myocardial ischemic preconditioning up-regulated protein 2 (GenBank accession number: AY221751). It has an open reading frame of 1497 bp, encoding a polypeptide of 498 amino acids with an N-terminal CTLH domain and 5 C-terminal WD40 repeats.
Using bioinformatics techniques it was found that MIP2 is an acidic protein with high hydrophobicity, but with no signal peptide. It contains four protein kinase C phophorylation sites, four N-glycosylation sites, seven casein kinaseⅡphosphorylation sites, indicating that the activation of MIP2 may be controlled by phosphorlation. Majority of its motifs are alpha helixs, extended strands and random coils in its secondary structure. Three-dimensional structure analysis showed that five WD-repeats of MIP2 form a propeller structure. SAGE (Several Analysis of Gene Expression) analysis revealed that MIP2 was ubiquitously expressed in normal human tissues and broad kinds of tumors, with a high expression in the heart.
We next observed the expression pattern of MIP2 in models of myocardial ischemia/reperfusion (I/R) and myocardial ischemic preconditioning (IP) in rats. The mRNA and protein expression levels were up-regulated after I/R, IP, IP+I/R and H2O2 exposure. A higher mRNA expression of the MIP2 was observed in ischemic myocardium than in non-ischemic myocardium. To observe the subcellular localization of MIP2, a pEGFP-MIP2 fusion vector was constructed. It was found that MIP2 was located mainly in the cytoplasm, with a part of MIP2 distributed on mitochondria.
It was also found that stable overexpression of MIP2 in rat cardiomyoblast cell line H9c2 resulted in an enhanced growth of the cells in a dose-dependant manner as measured by cell number. Overexpression of MIP2 resulted in a shorter cell cycle, as measured by flow cytometry. Collectively, these data suggested that MIP2 promoted the proliferation of H9c2 cells.
It was further found that oxidative stress induced by H2O2 led to concurrent increases in necrosis and apoptosis in cultured H9c2 rat cardiomyocytes. Overexpression of MIP2 decreased the cardiotoxicity induced by H2O2, which is associated with inhibition of the activation of caspase-9 and caspase-3, as well as inhibition of releasing of cytochrome C from mitochondrion to cytoplasm. MIP2 silencing increased oxidative stress-induced necrosis and apoptosis in H9C2 cells. These results indicated that MIP2 could protect cardiomyocytes against oxidative stress-induced injury.
引文
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[47]Henning KA, Li L, Iyer N, et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH [J]. Cell,1995,82 (4):555-564
[48]Introne W, Boissy RE, Gahl WA, Clinical, molecular, and cellbiological aspects of Chediak-Higashi syndrome [J]. Mol Genet Metab,1999,68 (2):283-303
[49]Guenther M G, Lane W S, Fischle W, et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness [J]. Genes Dev,2000,14(9):1048-1057
[50]Purdue PE, Lazarow PB. Peroxisome biogenesis [J]. Annu Rev Cell Dev Biol, 2001,17:701-752
[51]Cronshaw JM, Krutchinsky AN, Zhang W, et al. Proteomic analysis of the mammalian nuclear pore complex [J]. J Cell Biol,2002,158(5):915-927
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[53]Neer E.J., Schmidt C.J., Nambudripad R., Smith T.F., The ancient regulatory-protein family of WD-repeat proteins, Nature 1994,371:297-300.
[54]Yang P., Sale W.S., The Mr 140,000 intermediate Chain of Chlamydomonas Flagellar Inner Arm Dynein Is a WD-Repeat Protein Implicated in Dynein Arm Anchoring, Mol. Biol. Cell 1998,9:3335-3349.
[55]Ohnacker M., Barabino S.M., Preker P.J., Keller W., The WD-repeat protein Pfs2p bridges two essential factors within the yeast pre-mRNA 3'-end-processing complex, EMBO J.2000,19:37-47.
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[57]Ohtoshi A., Maeda T., Higashi H., Ashizawa S., Hatakeyama M., Human p55 (CDC)/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A-Cdk2 complex, Biochem. Biophys. Res. Commun.2000,268:530-534.
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[59]Chad M. McCall, Paula L, Miliani de Marval, et al. Human Immunodeficiency Virus Type 1 Vpr-Binding Protein VprBP, a WD40 Protein Assiated with the DDB1-CUL4 E3 Ubiquitin Ligase, Is Essential for DNA Replication and Embryonic Development. Mol. Cell Biol.2008,28:5621-5633.
[60]Zhao ZQ. Oxidative stress elicited myocardial apoptosis during reperfusion. Curr Opin Pharmacol,2004,4:159-165.
[61]Zweier JL. Measurement of superoxide derived free radicals in the reperfused heart:Evidence for a free radical mechanism of reperfusion injury. J Biol Chem, 1988,263:1353-1357.
[62]Hearse DJ, Humphrey SM, Chain EB. Abrupt reoxygenation of the anoxic potassium arrested perfused rat heart:a study of myocardial enzyme release. Mol Cell Cardiol,1973,5:395-407.
[63]Nordlie MA,Wold LE, Simkhovich BZ, et al. Molecular aspects of ischemic heart disease:ischemia/reperfusion induced genetic changes and potential applications of gene and RNA interference therapy. J Cardiovasc Pharmacol Ther, 2006,11:17-30.
[64]Yoshida H. Apaf-1 is required for mitochondrial pathways of apoptosis and brain development. Cell,2002,94:739-750
[65]Li J, Srinivasa M. Srinivasula, Feng TL, et al. Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemia cells. Blood, 2001,98:414-421
[66]Srinivasa MS, Ramesh H, Ayman S, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature, 2001,410:112-116
[1]Li D, Robert R. WD-repeat proteins:structure characteristics, biological function, and their involvement in human diseases [J]. Cell Mol Life Sci,2001,58 (14): 2085-2097
[2]Van Nocker S, Ludwig P. The WD-repeat protein superfamily in Arabidopsis: conservation and divergence in structure and function [J]. BMC Genomics,2003, 4(1):50
[3]Madrona AY, Wilson DK. The structure of Ski8p, a protein regulating mRNA degradation:Implications for WD protein structure [J]. Protein Sci,2004,13 (6): 1557-1565
[4]Smith T F, Gaitatzes C, Saxena K, et al. The WD repeat:a common architecture for diverse functions[J]. Trends Biochem Sci,1999,24 (5):181-185
[5]Tyers M, Willems AR. One ring to rule a superfamily of E3 ubiquitin ligases J]. Science,1999,284(5414):603-604
[6]Fong HK, Hurley JB, Hopkins R S, et al. Repetitive segmental structure of the transducinβ subunit:homology with the CDC4 gene and identification of related mRNAs[J]. Proc Natl Acad Sci USA,1986,83 (7):2162-2166
[7]Chothia C, Hubbard T, Brenner S, et al. Protein folds in the all-beta and all-alpha classes. Annu Rev Biophys Biomol Struct,1997,26:597-627
[8]Neer EJ, Schmidt CJ, Nambudripad R. and Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature,1994,371:297-300
[9]Yu LH, Gaitatzes C, Neer E, et al. Thirty-plus functional families from a single motif [J]. Protein Science,2000,9 (12):2470-2476
[10]Gao D, Wang R, et al. WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induces NF-κB activation pathway, Cell. Mol. Life Sci., 2009,66:2527-2584
[11]Roberts SG. Mechanisms of action of transcription activation and repression domains. Cell. Mol. Life Sci.2000,57:1149-1160
[12]Gratenstein K, Heggestad AD, Fortun J. et al. The WD-repeat protein GRWD1: Potential roles in myeloid differentiation and ribosome biogenesis. Genomics. 2005; 85(6):762-73.
[13]Li Q. and Suprenant K. A. Molecular characterization of the 77-kDa echinoderm microtubule-associated protein:homology to the beta-transducin family. J. Biol. Chem.1994,269:31777-31784
[14]Hendrickson TW, Perrone CA, Griffin P. et al. IC138 is a WD-repeat dynein intermediate chain required for light chain assembly and regulation of flagellar bending. Mol Biol Cell.2004; 15(12):5431-5442.
[15]Blacque OE, Li C, Inglis PN. et al. The WD Repeat-containing Protein IFTA-1 Is Required for Retrograde Intraflagellar Transport. MBC.2006; 17(12):5053-62.
[16]Luders J, Patel UK, Stearns T. GCP-WD is a gamma-tubulin targeting factor required for centrosomal and chromatin2mediated microtubule nucleation [J]. Nat Cell Biol,2006,8(2):137-147
[17]Zou H., Henzel WJ., Liu X., Lutschg A. and Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell,1997,90:405-413
[18]Suganuma T, Workman JL, WD40 repeats arrange histone tails for spreading of silencing, Journal of Molecular Cell Biology,2010,2:81-83
[19]Yaka R, Thornton C, Vagts A J, et al. NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1 [J]. Proc Natl Acad Sci USA,2002,99 (8): 5710-5715
[20]Thornton C, Tang KC, Phamluong K, et al. Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization [J]. J Biol Chem.,2004,279 (30):31357-31364
[21]Sklan EH, Podoly E, Soreq H. RACK1 has the nerve to act:Structure meets function in the nervous system[J]. Prog Neurobiol.2006,78(2):117-134
[22]Zhang W, Zong CS, Hermanto U, et al. RACK1 recruits STAT3 specifically to insulin and insulin-like growth factor 1 receptors for activation, which is important for regulating anchorage-2independent growth [J]. Mol Cell Biol.2006, 26(2):413-424
[23]Van der Voorn L, Ploegh HL. The WD-40 repeat [J]. FEBS Lett,1992,307 (2): 131-134
[24]段红英,丁笑生,孙富丛.WD重复蛋白.中国生物化学与分子生物学学报,2007,23(2)： 101-105
[25]Dell EJ, Connor J, Chen S, et al. The betagamma subunit of heterotrimeric G proteins interacts with RACK1 and two other WD repeat proteins [J]. J Biol Chem,2002,277(51):49888-49895
[26]Li X, Ji CN, Gu JF, et al. Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS [J]. Mol Biol Rep,2005,32(2):127-131
[27]Ridley AJ, Colley J, Wynford2Thomas D, et al. Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects [J]. J Hum Genet,2005,50 (3):151-154
[28]Pang CP, Fan BJ, Canlas O, et al. A genome2wide scan maps a novel juvenile-onset primary open angle glaucoma locus to chromosome 5q [J]. Mol Vis,2006,12:85-92
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[1]Li D, Robert R. WD-repeat proteins:structure characteristics, biological function, and their involvement in human diseases [J]. Cell Mol Life Sci,2001,58 (14): 2085-2097
[2]Van Nocker S, Ludwig P. The WD-repeat protein superfamily in Arabidopsis: conservation and divergence in structure and function [J]. BMC Genomics,2003, 4(1):50
[3]Madrona AY, Wilson DK. The structure of Ski8p, a protein regulating mRNA degradation:Implications for WD protein structure [J]. Protein Sci,2004,13 (6): 1557-1565
[4]Smith T F, Gaitatzes C, Saxena K, et al. The WD repeat:a common architecture for diverse functions[J]. Trends Biochem Sci,1999,24 (5):181-185
[5]Tyers M, Willems AR. One ring to rule a superfamily of E3 ubiquitin ligases J]. Science,1999,284(5414):603-604
[6]Fong HK, Hurley JB, Hopkins R S, et al. Repetitive segmental structure of the transducinβ subunit:homology with the CDC4 gene and identification of related mRNAs[J]. Proc Natl Acad Sci USA,1986,83 (7):2162-2166
[7]Chothia C, Hubbard T, Brenner S, et al. Protein folds in the all-beta and all-alpha classes. Annu Rev Biophys Biomol Struct,1997,26:597-627
[8]Neer EJ, Schmidt CJ, Nambudripad R. and Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature,1994,371:297-300
[9]Yu LH, Gaitatzes C, Neer E, et al. Thirty-plus functional families from a single motif [J]. Protein Science,2000,9 (12):2470-2476
[10]Gao D, Wang R, et al. WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induces NF-κB activation pathway, Cell. Mol. Life Sci., 2009,66:2527-2584
[11]Roberts SG. Mechanisms of action of transcription activation and repression domains. Cell. Mol. Life Sci.2000,57:1149-1160
[12]Gratenstein K, Heggestad AD, Fortun J. et al. The WD-repeat protein GRWD1: Potential roles in myeloid differentiation and ribosome biogenesis. Genomics. 2005; 85(6):762-73.
[13]Li Q. and Suprenant K. A. Molecular characterization of the 77-kDa echinoderm microtubule-associated protein:homology to the beta-transducin family. J. Biol. Chem.1994,269:31777-31784
[14]Hendrickson TW, Perrone CA, Griffin P. et al. IC138 is a WD-repeat dynein intermediate chain required for light chain assembly and regulation of flagellar bending. Mol Biol Cell.2004; 15(12):5431-5442.
[15]Blacque OE, Li C, Inglis PN. et al. The WD Repeat-containing Protein IFTA-1 Is Required for Retrograde Intraflagellar Transport. MBC.2006; 17(12):5053-62.
[16]Luders J, Patel UK, Stearns T. GCP-WD is a gamma-tubulin targeting factor required for centrosomal and chromatin2mediated microtubule nucleation [J]. Nat Cell Biol,2006,8(2):137-147
[17]Zou H., Henzel WJ., Liu X., Lutschg A. and Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell,1997,90:405-413
[18]Suganuma T, Workman JL, WD40 repeats arrange histone tails for spreading of silencing, Journal of Molecular Cell Biology,2010,2:81-83
[19]Yaka R, Thornton C, Vagts A J, et al. NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1 [J]. Proc Natl Acad Sci USA,2002,99 (8): 5710-5715
[20]Thornton C, Tang KC, Phamluong K, et al. Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization [J]. J Biol Chem.,2004,279 (30):31357-31364
[21]Sklan EH, Podoly E, Soreq H. RACK1 has the nerve to act:Structure meets function in the nervous system[J]. Prog Neurobiol.2006,78(2):117-134
[22]Zhang W, Zong CS, Hermanto U, et al. RACK1 recruits STAT3 specifically to insulin and insulin-like growth factor 1 receptors for activation, which is important for regulating anchorage-2independent growth [J]. Mol Cell Biol.2006, 26(2):413-424
[23]Van der Voorn L, Ploegh HL. The WD-40 repeat [J]. FEBS Lett,1992,307 (2): 131-134
[24]段红英,丁笑生,孙富丛.WD重复蛋白.中国生物化学与分子生物学学报,2007,23(2)： 101-105
[25]Dell EJ, Connor J, Chen S, et al. The betagamma subunit of heterotrimeric G proteins interacts with RACK1 and two other WD repeat proteins [J]. J Biol Chem,2002,277(51):49888-49895
[26]Li X, Ji CN, Gu JF, et al. Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS [J]. Mol Biol Rep,2005,32(2):127-131
[27]Ridley AJ, Colley J, Wynford2Thomas D, et al. Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects [J]. J Hum Genet,2005,50 (3):151-154
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