摘要
端粒是存在于真核生物线性染色体末端由核酸DNA重复序列和蛋白质组成的特殊保护性结构,端粒功能异常将导致细胞衰老和染色体不稳定性,是人类肿瘤发生的机制之一。中心体是高等真核生物细胞的主要微管组织中心,在细胞有丝分裂过程中起着至关重要的作用,与双极纺锤体的形成、纺锤体的定向和胞质分裂直接相关。中心体异常将损害细胞分裂的忠实性并导致染色体不稳定性。从低等生物到人都有实验证据证明端粒与细胞周期和有丝分裂之间存在密切联系,但目前具体介导端粒与细胞分裂之间相互关系的信号分子及功能尚不是很清楚。近年来研究发现TRF1在有丝分裂中期转位于纺锤体极点/中心体部位,而过量表达TRF1将促进细胞进入有丝分裂,提示TRF1可能是介导端粒和细胞分裂之间关系的信号分子。
在前期研究中,本课题组分离鉴定了一个新的TRF1相互作用蛋白并对该蛋白的细胞生物学功能进行了研究。结果显示该蛋白在细胞有丝分裂期定位于中心体,而siRNA基因干扰该蛋白会导致多极纺锤体形成,同时影响TRF1及Tankyrase1在中心体上的定位。根据该蛋白在有丝分裂期细胞的中心体定位以及siRNA敲除后对双极纺锤体形成的影响,我们将该蛋白命名为端粒相关的中心体蛋白1(Telomere associated centrosomal protein 1,TACP1)。
为更清楚的阐明TACP1在联系端粒和细胞有丝分裂中扮演的角色,本课题第一部分研究以TACP1全长为诱饵进行酵母双杂交筛库,试图寻找TACP1新的相互作用蛋白。通过酵母双杂交,我们得到23个可能的TACP1相互作用蛋白,生物信息学分析显示其中KIAA0649和HECTD3具有进一步研究的意义。进一步的酵母共转及体外Pull-down实验证实TACP1能和HECTD3 1-75相互作用。
泛素—蛋白酶体途径是目前已知的所有真核生物体内具有高度选择性的最为重要的蛋白降解途径,它通过选择性的降解蛋白,精确调控细胞内蛋白质的量,进而对许多重要的细胞生理功能(如细胞周期调控、凋亡等)起到调节作用。许多中心体蛋白表达水平随细胞周期进展而变化,其功能受到它们表达和降解的调控,而泛素—蛋白质酶体途径作为细胞内最主要的蛋白质降解途径,细胞周期相关蛋白多数通过这条途径降解。
前期我们的实验发现TACP1作为一个新的端粒相关中心体蛋白,是一个细胞周期性调节蛋白。为明确TACP1降解机制,本课题第二部分研究应用免疫共沉淀结合Western免疫印迹技术检测TACP1在体内是否发生泛素化修饰。结果显示TACP1在体内能发生泛素化修饰,而加入蛋白酶体抑制剂MG132后,TACP1泛素化修饰条带更为明显,说明TACP1在体内通过泛素—蛋白酶体途径降解。泛素—蛋白酶体途径最重要的特征就是底物的多样性和选择性,而这一功能是由泛素—蛋白连接酶E3s决定的。鉴于生物信息学分析显示HECTD3是一个含有HECT结构域的泛素—蛋白连接酶,其很可能是负责TACP1泛素化修饰的泛素—蛋白连接酶。为证实这个假设,本课题组设法得到HECTD3的全长,深入研究HECTD3对TACP1泛素化降解及功能的影响。酵母共转及生化实验证实TACP1和HECTD3存在相互作用,TACP1通过羧基端(332-476)和HECTD3相互作用,而HECTD3通过N端和TACP1相互作用;进一步研究显示HECTD3具有促进TACP1泛素化修饰的作用;HECTD3对体内TACP1蛋白的量具有负调控的作用,且该作用和其泛素—蛋白连接酶活性有关;而利用siRNA基因干扰抑制HECTD3蛋白表达将导致多极纺锤体的出现。综上所述,本部分研究证明TACP1通过泛素—蛋白酶体途径降解,而HECTD3作为负责TACP1泛素化修饰的泛素—蛋白连接酶,通过调控TACP1降解进而影响TACP1的功能,共同参与双极纺锤体的形成。通过上述研究,基本阐明了TACP1降解的具体机制,为深入理解TACP1在细胞有丝分裂特别是维持中心体稳定性中的作用提供新的实验佐证。
由于DNA聚合酶末端复制问题,每次细胞分裂端粒就会丢失50-150 bp,当端粒缩短至一定长度时(约4～5kb),细胞将不可逆地退出细胞周期进入复制性衰老继而死亡,因此端粒被认为是细胞的“有丝分裂钟”,其长度直接反映了细胞的增殖分裂潜能。为获得永生化的能力,绝大多数肿瘤细胞和永生化细胞系通过激活端粒酶来维持端粒长度,但部分神经上皮或间充质来源的肿瘤细胞如骨肉瘤、星形细胞瘤、里—费综合症,其端粒酶检测阴性。这些肿瘤细胞通过激活端粒延伸替代机制(Alternative lengthening of telomeres,ALT)从而弥补随细胞分裂而逐渐缩短的端粒长度。在ALT细胞中,存在一种特异性的ALT相关的PML小体(ALT-associated PML bodies,APBs)。ALT途径通过染色体重组来维持端粒长度,而APBs又是端粒重组的场所,故完整的APBs结构在ALT途径维持肿瘤细胞端粒长度,保持细胞永生化中扮演着重要角色,但目前有关APBs形成的具体机制尚不清楚。最近研究发现TRF1以及TRF1的SUMO化修饰和APBs的形成有关,但TRF1究竟是如何定位于APBs上,尚不清楚。
PML蛋白作为PML核小体(PML nuclear bodies,PNBs)最主要的组份,在PML核小体的形成中起到重要作用。根据PML基因外显子剪接方式的不同,PML共有7个拼接异构体PML1～7。目前有关PML各个异构体的研究尚不多,主要集中在PML3和PML4这两个异构体。研究显示,PML3能够将P53招募到PML核小体上进而促进P53的转录活性。
鉴于PML3的作用,我们设想在ALT细胞中TRF1通过和PML3的相互作用而被招募到PML核小体上。为证明这个假设,在本课题第三部分研究中,我们首先通过生化实验证实PML3和TRF1在体内外均有相互作用。进一步免疫荧光实验显示在ALT细胞中,TRF1和PML3共定位于APBs;TRF1在APBs上的定位和细胞周期密切相关,以G2/M期最高;外源性过表达PML3能招募TRF1上PML核小体;而利用siRNA基因干扰抑制内源性PML3蛋白表达,不仅会抑制TRF1在APBs上的定位,对TRF2在APBs上的定位也有影响,提示PML3对于APBs的形成至关重要。本研究首次发现PML3具有招募TRF1上PML核小体的作用,且PML3对于APBs的形成至关重要,为阐明ALT相关PML小体形成的分子机制提供新的实验证据。
综上所述,本研究可分为两个部分。在第一、二部分研究中,我们首次发现TACP1通过泛素—蛋白酶体途径降解,而HECTD3作为负责TACP1泛素化修饰的泛素—蛋白连接酶,通过调控TACP1降解进而影响TACP1的功能,共同参与双极纺锤体的形成。通过研究,基本阐明了TACP1降解的具体机制,为深入理解TACP1在细胞有丝分裂特别是维持中心体稳定性中的作用提供新的实验佐证。而本课题第三部分研究首次发现PML3具有招募TRF1上PML核小体的作用,且PML3对于APBs的形成至关重要,为阐明ALT相关PML小体形成的分子机制提供新的实验证据。
Telomeres are specialized protective structures at the extreme ends of linearly eukaryotic chromosomes.Telomere dysfunction is associated with chromosomal instability which is implicated in ageing and carcinogenesis.Centrosomes,the principal microtubule organizing center(MTOC)in nearly all higher eukaryotic cells, have a pivotal role in regulating cell division in mitotic cells.During mitosis, centrosomes govern assembly and orientation of the bipolar mitotic spindle that is essential for correct chromosome segregation and cytokinesis.Centrosome aberrations may compromise the fidelity of cell division and cause chromosomal instability.There is compelling evidence to suggest a strong link between telomere maintenance and cell cycle control,especially mitotic regulation.However,little is known about the identity and function of the signaling molecule(s)connecting telomere maintenance and mitotic regulation.Recent studies showed that TRF1 translocates to centrosome and/or spindle pole during mitosis and TRF1 overexpression induces mitotic entry in cells with short telomeres,suggesting the role of TRF1 in mitotic regulation by providing a functional link between telomere and centrosome.
In our previous study,a novel TRF1 interacting protein was identified from mitotic HeLa cell lysates by employing immunoaffinity isolatin and mass spectrometry(MS).We refer to the protein as Telomere Associated Centrosomal Protein 1(TACP1)since it distinguishes from other TRF1 binding proteins and traffics toward centrosome during mitosis.Further studies revealed that depletion of TACP1 by small interfering RNA leads to multipolar spindle formation and abolishes the centrosomal localization of TRF1 and Tankyrase 1.
To further elucidate the role of TACP1 in connecting telomere maintenance and mitotic regulation,we performed a yeast two-hybrid screen with TACP1 as a bait and identified 23 novel TACP1-binding proteins including KIAA0649 and HECTD3. Further yeast co-transformation assay and pull-dwon assay confirmed the interaction between TACP1 and HECTD3 1-75.
The ubiquitin-proteasome system,the most important protein degradation pathway in eukaryotic cells,regulates a host of critical cellular functions such as cell cycle progression and apoptosis through mediating the selective and time-dependent degradation of short-lived regulatory proteins.Many centrosomal proteins are regulated in a cell cycle-dependent fashion,and most of them are degraded through ubiqultin-proteasome pathway.
Our previous studies showed that TACP1,as a novel telomere associated centrosomal protein,is a cell cycle-regulated protein.To clarify the degradation mechanism of TACP1,we carded out in vivo ubiquitination assay to determine whether TACP1 is ubiquitinated in vivo.The results showed that TACP1 is ubiquitinated in vivo and treatment of cells with the proteasome inhibitor MG132 causes a robust increase of TACP1 ubuiquitination,suggesting that TACP1 is the substrate for proteasome.In the ubiquitin-proteasome system,the selectivity of substrate appears to be determined through interaction between specific ubiquitin-protein ligase(E3)and substrate.According to computational analysis,we hypothesized that HECTD3,a putative member of HECT E3 ubiquitin ligases,is a specific E3 ligase for TACP1.To confirm this hypothesis,we first validated that TACP1 interacts with HECTD3 in vitro and in vivo.Further studies showed that HECTD3 overexpression enhances the ubiquitination of TACP1 and promotes the turnover of TACP1,where depletion of HECTD3 decreases TACP1 degradation. More notably,depletion of TACP1 leads to multipolar spindle formation.All these findings suggest that HECTD3 is a specific E3 ligase for TACP1 and may facilitate cell cycle progression via regulation ubiquitination and degradation of TACP1.
In normal somatic human cells,telomeres shorten by 50-150 base pairs(bp)per cell division owing to the end-replication problem of the lagging strand,which ultimately leads to replicative senescence when the telomere length reaches a critical point(4～5 kb).Therefore,telomeres have been proposed to act as a counting mechanism for cellular proliferation.To achieve unlimited replicative potential,most cancer cells activate telomerase to elongate telomeres.However,some cancer cells, including sarcomas,astrocytomas,and tumors of Li-Fraumeni syndrome,cannot activate telomerase and use telomere homologous recombination to elongate telomeres,a mechanism termed altemative lengthening of telomeres(ALT).A hallmark of ALT cells is the presence of ALT-associated PML bodies(APBs).It has been suggested that APBs may have an integral role in the ALT mechanism,but the exact mechanism of APBs formation remains unclear.Recent studies revealed that TRF1 and its sumoylation is essential for the formation of APBs,but the detailed mechanism of the recruitment of TRF1 to APBs is unknown.
PML,as the most prominent component of PML nuclear bodies(PNBs),has a fundamental role in assembly of PML nuclear bodies.According to C-terminal sequence variation,seven PML isoforms have been identified.Up to date,most studies on these isoforms concentrate on PML3,which has been shown to recruit P53 to PML nuclear bodies and increase its transcriptional activity.
Taking the function of PML3,we hypothesized that PML3 may assist the recruitment of TRF1 to APBs.To confirmed this,we first validated the interaction between PML3 and TRF1 by co-immunoprecipitation and GST pull-down assays. Immunofluorescence studies showed that TRF1 colocalizes with PML3 at APBs in a subset of ALT cells and the percentage of cells with co-localization of TRF1 with APBs greatly increased in cells enriched in G2/M.Further studies revealed that overexpression of PML3 strengthens the localization of TRF1 to PML nuclear bodies, while depletion of PML3 inhibits the recruitment of TRF1 and TRF2 to APBs.Taken together,our results suggest that PML3 interacts with TRF1 and is essential for APBs formation.
引文
[1] Blackburn EH. Structure and function of telomeres. Nature, 1991;350:569-573.
[2] Blackburn EH. Switching and signaling at the telomere. Cell, 2001;106:661-673.
[3] Crabbe L, Karlseder J. In the end, it's all structure. Curr Mol Med, 2005;5:135-143.
[4] de Lange T. Protection of mammalian telomeres. Oncogene, 2002;21:532-540.
[5] de Lange T. CELL BIOLOGY: Enhanced: Telomere Capping-One Strand Fits All. Science, 2001;292:1075-1076.
[6] Baumgartner BL, Lundblad V. Telomere identity crisis. Genes Dev, 2005;19:2522-2525.
[7] Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet, 2005;6:611-622.
[8] Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest, 2004;113:160-168.
[9] Gilley D, Tanaka H, Herbert BS. Telomere dysfunction in aging and cancer. Int J Biochem Cell Biol, 2005;37:1000-1013.
[10] Doxsey S. Re-evaluating centrosome function. Nat Rev Mol Cell Biol, 2001;688-698.
[11] Job D, Valiron O, Oakley B. Microtubule nucleation. Curr Opin Cell Biol, 2003,15:111-117.
[12] Doxsey S, Zimmerman W, Mikule K. Centrosome control of the cell cycle. Trends Cell Biol, 2005;15:303-311.
[13] Lopes CS, Sunkel CE. The spindle checkpoint: from normal cell division to tumorigenesis. Arch Med Res,2003;34:155-165.
[14] Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature, 2004;432:338-341.
[15] Sandell LL, Zakian VA. Loss of a yeast telomere: Arrest, recovery, and chromosome loss. Cell, 1993;75:729-739.
[16] Chikashige Y, Ding DQ, Funabiki H, et al. Telomere-led premeiotic chromosome movement in fission yeast. Science, 1994;264:270-273.
[17] Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics, 1999;151:1041-1051.
[18] Kirk KE, Harmon BP, Reichardt IK, et al. Block in anaphase chromosome separation caused by a telomerase template mutation. Science, 1997;275:1478-1481.
[19] Smilenov LB, Morgan SE, Mellado W, et al. Influence of ATM function on telomere metabolism. Oncogene, 1997;15:2659-2665.
[20] Chang P, Coughlin M, Mitchison TJ. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nat Cell Biol, 2005;7:l 133-1139.
[21] Nakamura M, Zhou XZ, Kishi S, et al. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol, 2001 ;11:1512-1516.
[22] Smith S, de Lange T. Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes. J Cell Sci, 1999;] 12 (Pt 21):3649-3656.
[23] Zhou XZ, Perrem K, Lu KP. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem, 2003 ;89:19-37.
[24] Xu L, Blackburn EH. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. J Cell Biol, 2004;167:819-830.
[25] Chong L, van Steensel B, Broccoli D, et al. A human telomeric protein. Science, 1995;270:1663-1667.
[26] Bianchi A, Smith S, Chong L, et al. TRF1 is a dimer and bends telomeric DNA. Embo J, 1997;16:1785-1794.
[27] Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell, 1999;97:503-514.
[28] van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature, 1997;385:740-743.
[29] Nakamura M, Zhou XZ, Kishi S, et al. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett, 2002;514:193-198.
[30] Kishi S, Lu KP. A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells. J Biol Chem, 2002;277:7420-7429.
[31] Grallert A, Hagan IM. Schizosaccharomyces pombe NIMA-related kinase, Finl, regulates spindle formation and an affinity of Polo for the SPB. EMBO J, 2002;21:3096-3107.
[32] Prime G, Markie D. The telomere repeat binding protein Trfl interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase. Cell Cycle, 2005 ;4.
[33] Cooper JP, Nimmo ER, Allshire RC, et al. Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature, 1997;385:744-747.
[34] Flory MR, Carson AR, Muller EG, et al. An SMC-Domain Protein in Fission Yeast Links Telomeres to the Meiotic Centrosome. Mol Cell, 2004; 16:619-630.
[35] Bornens M. Centrosome composition and microtubule anchoring mechanisms. Curr Opin Cell Biol, 2002;14:25-34.
[36] Delattre M, Gonczy P. The arithmetic of centrosome biogenesis. J Cell Sci, 2004; 117:1619-1630.
[37] Ou Y, Rattner JB. The centrosome in higher organisms: structure, composition, and duplication. Int Rev Cytol, 2004;238:119-182.
[38] Shen M, Haggblom C, Vogt M, et al. Characterization and cell cycle regulation of the related human telomeric proteins Pin2 and TRF1 suggest a role in mitosis. Proc Natl Acad Sci U S A, 1997;94:13618-13623.
[39] Kishi S, Wulf G, Nakamura M, et al. Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors. Oncogene, 2001;20:1497-1508.
[40] Broccoli D, Smogorzewska A, Chong L, et al. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet, 1997; 17:231-235.
[41] Court R, Chapman L, Fairall L, et al. How the human telomeric proteins TRF1 and TRF2 recognize telomeric DNA: a view from high-resolution crystal structures. EMBO Rep, 2005;6:39-45.
[42] Tomaska L, Willcox S, Slezakova J, et al. Tazl binding to a fission yeast model telomere: formation of t-loops and higher order structures. J Biol Chem, 2004.
[43] Flory MR, Morphew M, Joseph JD, et al. Pcplp, an Spell Op-related calmodulin target at the centrosome of the fission yeast Schizosaccharomyces pombe. Cell Growth Differ, 2002; 13:47-58.
[44] Fields S, Stemglanz R. The two-hybrid system: an assay for protein-protein interactions. Trends Genet, 1994;10:286-292.
[45] Harper JW, Adami GR, Wei N, et al. The p21 Cdk-interacting protein Cipl is a potent inhibitor of Gl cyclin-dependent kinases. Cell, 1993;75:805-816.
[46] Bemis LT, Geske FJ, Strange R. Use of the yeast two-hybrid system for identifying the cascade of protein interactions resulting in apoptotic cell death. Methods Cell Biol, 1995;46:139-151.
[47]Spaargaren M,Martin GA,McCormick F,et al.The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner.Bioehem J,1994;300(Pt 2):303-307.
[48]Rossignol M,Kolb-Cheynel I,Egly JM.Substrate specificity of the cdk-activating kinase(CAK)is altered upon association with TFIIH.EMBO J,1997;16:1628-1637.
[49]Yang L,Zhao J,Lu W,et al.KIAA0649,a 1A6/DRIM-interacting protein with the oncogenic potential.Biochem Biophys Res Commun,2005;334:884-890.
[50]Marcelain K,Hayman MJ.The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis.Oneogene,2005;24:4321-4329.
[51]Wang Y,Zhan Q.Cell cycle-dependent expression of centrosomal ninein-like protein in human cells is regulated by the anaphase-promoting complex.J Biol Chem,2007;282:17712-17719.
[52]Huibregtse JM,Yang JC,Beaudenon SL.The large subunit of RNA polymerase Ⅱ is a substrate of the Rsp5 ubiquitin-protein ligase.Proc Natl Acad Sci U S A,1997;94:3656-3661.
[1]Hershko A,Ciechanover A,Varshavsky A.Basic Medical Research Award.The ubiquitin system.Nat Med,2000;6:1073-1081.
[2]Reed SI.The ubiquitin-proteasome pathway in cell cycle control.Results Probl Cell Differ,2006;42:147-181.
[3]Nakayama KI,Nakayama K.Regulation of the cell cycle by SCF-type ubiquitin ligases.Semin Cell Dev Biol,2005;16:323-333.
[4]Orlowski RZ.The role of the ubiquitin-proteasome pathway in apoptosis.Cell Death Differ,1999;6:303-313.
[5]Zhang HG,Wang J,Yang X,et al.Regulation of apoptosis proteins in cancer cells by ubiquitin.Oneogene,2004;23:2009-2015.
[6]Hoeller D,Hecker CM,Dikic I.Ubiquitin and ubiquitin-like proteins in cancer pathogenesis.Nat Rev Cancer,2006;6:776-788.
[7]Chen ZJ.Ubiquitin signalling in the NF-kappaB pathway.Nat Cell Biol,2005;7:758-765.
[8]d'Azzo A,Bongiovanni A,Nastasi T.E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation.Traffic,2005;6:429-441.
[9]Tanowitz M,Von Zastrow M.Ubiquitination-independent trafficking of G protein-coupled receptors to lysosomes.J Biol Chem,2002;277:50219-50222.
[10]Sun ZW,Allis CD.Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.Nature,2002;418:104-108.
[11]Muratani M,Kung C,Shokat KM,et al.The F box protein Dsgl/Mdm30 is a transcriptional coactivator that stimulates Ga14 turnover and cotrancriptional mRNA processing.Cell,2005;120:887-899.
[12]Xirodimas DP,Saville MK,Bourdon JC,et al.Mdm2-mediated NEDD8 conjugation of p53inhibits its transcriptional activity.Cell,2004;118:83-97.
[13]Spence J,Gall RR,Dittmar G,et al.Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain.Cell,2000;102:67-76.
[14]Nijman SM,Huang TT,Dime AM,et al.The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.Mol Cell,2005;17:331-339.
[15]D'Andrea AD,Grompe M.The Fanconi anaemia/BRCA pathway.Nat Rev Cancer,2003;3:23-34.
[16]Linggi B,Muller-Tidow C,van de Locht L,et al.The t(8;21)fusion protein,AML1 ETO,specifically represses the transcription of the p14(ARF)tumor suppressor in acute myeloid leukemia.Nat Med,2002;8:743-750.
[17]Pomerantz J,Schreiber-Agus N,Liegeois NJ,et al.The Ink4a tumor suppressor gene product,p19Arf,interacts with MDM2 and neutralizes MDM2's inhibition of p53.Cell,1998;92:713-723.
[18]Bahram F,von der Lehr N,Cetinkaya C,et al.c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover.Blood,2000;95:2104-2110.
[19]Smalle J,Vierstra RD.The ubiquitin 26S proteasome proteolytic pathway.Annn Rev Plant Biol,2004;55:555-590.
[20]Robinson PA,Ardley HC.Ubiquitin-protein ligases.J Cell Sci,2004;117:5191-5194.
[21]Hatakeyama S,Nakayama KI.U-box proteins as a new family of ubiquitin ligases.Biochem Biophys Res Commnn,2003;302:635-645.
[22] Marcelain K, Hayman MJ. The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis. Oncogene, 2005;24:4321-4329.
[23] Wang Y, Zhan Q. Cell cycle-dependent expression of centrosomal ninein-like protein in human cells is regulated by the anaphase-promoting complex. J Biol Chem, 2007282:17712-17719.
[24] King RW, Deshaies RJ, Peters J-M, et al. How proteolysis drives the cell cycle. Science, 1996;274:1652-1659.
[25] Huibregtse JM, Yang JC, Beaudenon SL. The large subunit of RNA poh/merase II is a substrate of the Rsp5 ubiquitin-protein ligase. Proc Natl Acad Sci U S A, 1997;94:3656-3661.
[26] Simpson MV. The release of labeled amino acids from the proteins of rat liver slices. J Biol Chem, 1953201:143-154.
[27] Etlinger JD, Goldberg AL. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A, 1977;74:54-58.
[28] Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun, 1978;81:1100-1105.
[29] Wilkinson KD, Urban MK, Haas AL. Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes. J Biol Chem, 1980;255:7529-7532.
[30] Ciechanover A, Heller H, Elias S, et al. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc Natl Acad Sci U S A, 1980;77:1365-1368.
[31] Hershko A, Ciechanover A, Heller H, et al. Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc Natl Acad Sci U S A, 1980;77:1783-1786.
[32] Ciechanover A, Heller H, Katz-Etzion R, et al. Activation of the heat-stable polypeptide of the ATP-dependent proteolytic system. Proc Natl Acad Sci U S A, 1981;78:761-765.
[33] Ciechanover A, Elias S, Heller H, et al. "Covalent affinity" purification of ubiquitin-activating enzyme. J Biol Chem, 1982;257:2537-2542.
[34] Hershko A, Heller H, Elias S, et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem, 1983;258:8206-8214.
[35] Hough R, Pratt G, Rechsteiner M. Ubiquitin-lysozyme conjugates. Identification and characterization of an ATP-dependent protease from rabbit reticulocyte lysates. J Biol Chem, 1986;261:2400-2408.
[36] Hough R, Pratt G, Rechsteiner M. Purification of two high molecular weight proteases from rabbit reticulocyte lysate. J Biol Chem, 1987262:8303-8313.
[37] Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer, 2006;6:369-381.
[38] Huibregtse JM, Scheffner M, Beaudenon S, et al. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci U S A, 1995;92:2563-2567.
[39] Scheffiier M, Nuber U, Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature, 1995;373:81-83.
[40] Doxsey S. Re-evaluating centrosome function. Nat Rev Mol Cell Biol, 20012:688-698.
[41] Job D, Valiron O, Oakley B. Microtubule nucleation. Curr Opin Cell Biol, 2003;15:l 11-117.
[42] Doxsey S, Zimmerman W, Mikule K. Centrosome control of the cell cycle. Trends Cell Biol, 2005;15:303-311.
[43] Lopes CS, Sunkel CE. The spindle checkpoint: from normal cell division to tumorigenesis. Arch Meal Res,2003;34:155-165.
[44]Rajagopalan H,Lengauer C.Aneuploidy and cancer.Nature,2004;432:338-341.
[45]FabunmiRP,WigleyWC,ThomasPJ,etal.ActivityandRegulation of the Centrosome-associated Proteasome.J Biol Chem,2000;275:409-413.
[46]Freed E,Lacey KR,Huie P,et al.Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle.Genes Dev,1999;13:2242-2257.
[47]Gstaiger M,Marti A,Krek W.Association of human SCF(SKP2)subunit p19(SKP1)with interphase centrosomes and mitotic spindle poles.Exp Cell Res,1999;247:554-562.
[48]Hansen DV,Hsu JY,Kaiser BK,et al.Control of the centriole and centrosome cycles by ubiquitination enzymes.Oncogene,2002;21:6209-6221.
[49]Carroll PE,Okuda M,Hom HF,et al.Centrosome hyperamplification in human cancer:chromosome instability induced by p53 mutation and/or Mdm2 overexpression.Oneogene,1999;18:1935-1944.
[50]Tarapore P,Fukasawa K.Loss of p53 and centrosome hyperamplification.Oncogene,2002;21:6234-6240.
[51]Sbodio JI,Lodish HF,Chi NW.Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1(telomere-repeat-binding factor 1)and IRAP(insulin-responsive aminopeptidase).Bioehem J,2002;361:451-459.
[52]Cook BD,Dynek JN,Chang W,et al.Role for the related poly(ADP-Ribose)polymerases tankyrase 1 and 2 at human telomeres.Mol Cell Biol,2002;22:332-342.
[53]Smith S,de Lange T.Tankyrase promotes telomere elongation in human cells.Cnrr Biol,2000;10:1299-1302.
[54]Smith S,de Lange T.Cell cycle dependent localization of the telomeric PARP,tankyrase,to nuclear pore complexes and centrosomes.J Cell Sci,1999;112(Pt 21):3649-3656.
[55]Chang P,Jacobson MK,Mitchison TJ.Poly(ADP-ribose)is required for spindle assembly and structure.Nature,2004;432:645-649.
[56]Chang P,Coughlin M,Mitchison TJ.Tankyrase-1 polymerization of poly(ADP-fibose)is required for spindle structure and function.Nat Cell Biol,2005;7:1133-1139.
[1]Blackburn EH.Structure and function of telomeres.Nature,1991;350:569-573.
[2]Blackburn EH.Switching and signaling at the telomere.Cell,2001;106:661-673.
[3]Crabbe L,Karlseder J.In the end,it's all structure.Curt Mol Med,2005;5:135-143.
[4]de Lange T.Protection of mammalian telomeres.Oncogene,2002;21:532-540.
[5]de Lange T.CELL BIOLOGY:Enhanced:Telomere Capping-One Strand Fits All.Science,2001;292:1075-1076.
[6]Baumgartner BL,Lundblad V.Telomere identity crisis.Genes Dev,2005;19:2522-2525.
[7]Blasco /MA.Telomeres and human disease:ageing,cancer and beyond.Nat Rev Genet,2005;6:611-622.
[8]Olovnikov AM.A theory of marginotomy.The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon.J Theor Biol,1973;41:181-190.
[9]Allsopp RC,Chang E,Kashefi-Aazam M,et al.Telomere shortening is associated with cell division in vitro and in vivo.Exp Cell Res,1995;220:194-200.
[10]de Magalhaes JP.From cells to ageing:a review of models and mechanisms of cellular senescence and their impact on human ageing.Exp Cell Res,2004;300:1-10.
[11]Harley CB.Telomere loss:mitotic clock or genetic time bomb? Mutat Res,1991;256:271-282.
[12]Harley CB,Further AB,Greider CW.Telomeres shorten during ageing of human fibroblasts.Nature,1990;345:458-460.
[13]Allsopp RC,Vaziri H,Patterson C,et al.Telomere length predicts replicative capacity of human fibroblasts.Proe Natl Acad Sci LISA,1992;89:10114-10118.
[14]Kim NW,Piatyszek MA,Prowse KR,et al.Specific association of human telomerase activity with immortal cells and cancer.Science,1994;266:2011-2015.
[15]Shay JW,Bacchetti S.A survey of telomerase activity in human cancer.Eur J Cancer,1997;33:787-791.
[16]Meyerson M,Counter CM,Eaton EN,et al.hEST2,the putative human telomerase catalytic subunit gene,is up-regulated in tumor cells and during immortalization.Cell,1997;90:785-795.
[17]Bryan TM,Englezou A,Dalla-Pozza L,et al.Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.Nat Med,1997;3:1271-1274.
[18]Henson JD,Hannay JA,McCarthy SW,et al.A robust assay for alternative lengthening of telomeres in tumors shows the significance of altemative lengthening of telomeres in sarcomas and astrocytomas.Clin Cancer Res,2005;11:217-225.
[19]Bryan TM,Englezou A,Gupta J,et al.Telomere elongation in immortal human cells without detectable telomerase activity.Embo J,1995;14:4240-4248.
[20]Muntoni A,Reddel RR.The first molecular details of ALT in human tumor cells.Hum Mol Genet,2005;14 Spec No.2:R191-196.
[21]Henson JD,Neumann AA,Yeager TR,et al.Alternative lengthening of telomeres in mammalian cells.Oncogene,2002;21:598-610.
[22]Yeager TR,Neumann AA,Englezou A,et al.Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia(PML)body.Cancer Res,1999;59:4175-4179.
[23]Hofinann TG,Will H.Body language:the function of PML nuclear bodies in apoptosis regulation. Cell Death Differ, 2003;10:1290-1299.
[24] Wu G, Jiang X, Lee WH, et al. Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1. Cancer Res, 2003;63:2589-2595.
[25] Johnson FB, Marciniak RA, McVey M, et al. The Saccharomyces cerevisiae WRN homolog Sgslp participates in telomere maintenance in cells lacking telomerase. EMBO J, 2001;20:905-913.
[26] Stavropoulos DJ, Bradshaw PS, Li X, et al. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum Mol Genet, 2002;11:3135-3144.
[27] Yankiwski V, Marciniak RA, Guarente L, et al. Nuclear structure in normal and Bloom syndrome cells. Proc Natl Acad Sci U S A, 2000;97:5214-5219.
[28] Wu G, Lee WH, Chen PL. NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J Biol Chem, 2000;275:30618-30622.
[29] Jiang WQ, Zhong ZH, Henson JD, et al. Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. Mol Cell Biol, 2005;25:2708-2721.
[30] Zhong ZH, Jiang WQ, Cesare AJ, et al. Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres. J Biol Chem, 2007;282:29314-29322.
[31] Naka K, Ikeda K, Motoyama N. Recruitment of NBS1 into PML oncogenic domains via interaction with SP100 protein. Biochem Biophys Res Commun, 2002;299:863-871.
[32] Potts PR, Yu H. The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. Nat Struct Mol Biol, 2007;14:581-590.
[33] Jiang WQ, Zhong ZH, Henson JD, et al. Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference. Oncogene, 2007;26:4635-4647.
[34] Zhong S, Muller S, Ronchetti S, et al. Role of SUMO-1-modified PML in nuclear body formation. Blood, 2000;95:2748-2752.
[35] Jensen K, Shiels C, Freemont PS. PML protein isoforms and the RBCC/TRIM motif. Oncogene, 2001;20:7223-7233.
[36] Fogal V, Gostissa M, Sandy P, et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J, 2000;19:6185-6195.
[37] Grobelny JV, Godwin AK, Broccoli D. ALT-associated PML bodies are present in viable cells and are enriched in cells in the G(2)/M phase of the cell cycle. J Cell Sci, 2000;l 13 Pt 24:4577-4585.
[38] Xu ZX, Zou WX, Lin P, et al. A role for PML3 in centrosome duplication and genome stability. Mol Cell, 2005;17:721-732.
[39] Wright WE, Tesmer VM, Huffman KE, et al. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev, 1997;11:2801-2809.
[40] Makarov VL, Hirose Y, Langmore JP. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell, 1997;88:657-666.
[41] Lundblad V, Blackburn EH. An alternative pathway for yeast telomere maintenance rescues estl- senescence. Cell, 1993;73:347-360.
[42] Dunham MA, Neumann AA, Fasching CL, et al. Telomere maintenance by recombination in human cells. Nat Genet, 2000;26:447-450.
[43] Londono-Vallejo JA, Der-Sarkissian H, Cazes L, et al. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res, 2004;64:2324-2327.
[44]Rogan EM,Bryan TM,Hukku B,et al.Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts.Mol Cell Biol,1995;15:4745-4753.
[45]Dellaire G,Bazett-Jones DP.PML nuclear bodies:dynamic sensors of DNA damage and cellular stress.Bioessays,2004;26:963-977.
[46]Hodges M,Tissot C,Howe K,et al.Structure,organization,and dynamics of promyelocytic leukemia protein nuclear bodies.Am J Hum Genet,1998;63:297-304.
[1]Smalle J,Vierstra RD.The ubiquitin 26S proteasome proteolytic pathway.Anna Rev Plant Biol,2004;55:555-590.
[2]Welchman RL,Gordon C,Mayer RJ.Ubiquitin and ubiquitin-like proteins as multifunctional signals.Nat Rev Mol Cell Biol,2005;6:599-609.
[3]Pickart CM.Ubiquitin in chains.Trends Bioehem Sci,2000;25:544-548.
[4]Pickart CM.Mechanisms underlying ubiquitination.Annu Rev Bioehem,2001;70:503-533.
[5]Goldstein G,Scheid M,Hammerling U,et al.Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells.Proe Nail Acad Sci U S A,1975;72:11-15.
[6]Schlesinger DH,Goldstein G,Niall HD.The complete amino acid sequence of ubiquitin,an adenylate cyclase stimulating polypeptide probably universal in living cells.Biochemistry,1975;14:2214-2218.
[7]Wilkinson KD,Urban MK,Haas AL.Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes.J Biol Chem,1980;255:7529-7532.
[8]Vijay-Kumar S,Bugg CE,Wilkinson KD,et al.Three-dimensional structure of ubiquitin at 2.8 A resolution.Proe Natl Acad Sci U S A,1985;82:3582-3585.
[9]Wilkinson KD,Audhya TK.Stimulation of ATP-dependent proteolysis requires ubiquitin with the COOH-terminal sequence Arg-Gly-Gly.J Biol Chem,1981;256:9235-9241.
[10]Cook JC,Chock PB.Isoforms of mammalian ubiquitin-activating enzyme.J Biol Chem,1992;267:24315-24321.
[11]Handley-Gearhart PM,Stephen AG,Trausch-Azar JS,et al.Human ubiquitin-activating enzyme,El.Indication of potential nuclear and cytoplasmic subpopulations using epitope-tagged eDNA constructs.J Bioi Chem,1994;269:33171-33178.
[12]Stephen AG,Trausch-Azar JS,Ciechanover A,et al.The ubiquitin-activating enzyme El is phosphorylated and localized to the nucleus in a cell cycle-dependent manner.J Biol Chem,1996;271:15608-15614.
[13]Haas AL,Rose IA.The mechanism of ubiquitin activating enzyme.A kinetic and equilibrium analysis.J Biol Chem,1982;257:10329-10337.
[14]Hershko A,Heller H,Elias S,et al.Components of ubiquitin-protein ligase system.Resolution,affinity purification,and role in protein breakdown.J Bioi Chem,1983;258:8206-8214.
[15]McGrath JP,Jentsch S,Varshavsky A.UBA 1:an essential yeast gene encoding ubiquitin-activating enzyme.EMBO J,1991;10:227-236.
[16]Sullivan ML,Vierstra RD.Cloning of a 16-kDa ubiquitin carrier protein from wheat and Arabidopsis thaliana.Identification of functional domains by in vitro mutagenesis.J Biol Chem,1991;266:23878-23885.
[17]Sung P,Prakash S,Prakash L.Mutation of cysteine-88 in the Saccharomyces cerevisiae RAD6protein abolishes its ubiquitin-conjugating activity and its various biological functions.Proe Natl Acad Sci U S A,1990;87:2695-2699.
[18]Sung P,Prakash S,Prakash L.Stable ester conjugate between the Saccharomyces cerevisiae RAD6 protein and ubiquitin has no biological activity.J Mol Biol,1991;221:745-749.
[19]Mathias N,Steussy CN,Goebl MG.An essential domain within Cdc34p is required for binding to a complex containing Cdc4p and Cdc53p in Saccharomyces cerevisiae.J Biol Chem,1998;273:4040-4045.
[20] Robinson PA, Ardley HC. Ubiquitin-protein ligases. J Cell Sci, 2004;l 17:5191-5194.
[21] Hatakeyama S, Nakayama KI. U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun, 2003;302:635-645.
[22] Schefmer M, Huibregtse JM, Vierstra RD, et al. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell, 1993;75:495-505.
[23] Huibregtse JM, Scheffner M, Beaudenon S, et al. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci U S A, 1995;92:2563-2567.
[24] Scheffher M, Nuber U, Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin Ihioester cascade. Nature, 1995;373:81-83.
[25] Huibregtse JM, Yang JC, Beaudenon SL. The large subunit of RNA polymerase II is a substrate of the Rsp5 ubiquitin-protein ligase. Proc Natl Acad Sci U S A, 1997;94:3656-3661.
[26] Huibregtse JM, Scheffher M, Howley PM. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol, 1993;13:775-784.
[27] Wang G, Yang J, Huibregtse JM. Functional domains of the Rsp5 ubiquitin-protein ligase. Mol Cell Biol, 1999;19:342-352.
[28] Sudol M, Bork P, Einbond A, et al. Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem, 1995270:14733-14741.
[29] Sudol M, Chen HI, Bougeret C, et al. Characterization of a novel protein-binding module-the WW domain. FEBS Lett, 1995;369:67-71.
[30] Kay BK, Williamson MP, Sudol M. The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J, 2000;14:231-241.
[31] Kamynina E, Debonneville C, Bens M, et al. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J, 2001;15:204-214.
[32] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases. J Membr Biol, 2000;176:l-17.
[33] Staub O, Dho S, Henry P, et al. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J, 1996;15:2371-2380.
[34] Staub O, Gautschi I, Ishikawa T, et al. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J, 1997;16:6325-6336.
[35] Schild L, Lu Y, Gautschi I, et al. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J,1996;15:2381-2387.
[36] Freemont PS. RING for destruction? Curr Biol, 2000;10:R84-87.
[37] Joazeiro CA, Weissman AM. RING ringer proteins: mediators of ubiquitin ligase activity. Cell, 2000;102:549-552.
[38] Saurin AJ, Borden KL, Boddy MN, et al. Does this have a familiar RING? Trends Biochem Sci, 1996;21:208-214.
[39] Zheng N, Wang P, Jeffrey PD, et al. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell, 2000;102:533-539.
[40] Rubin C, Gur G, Yarden Y. Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation. Cell Res, 2005;15:66-71.
[41]Fang S,Jensen JP,Ludwig RL,et al.Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.J Biai Chem,2000;275:8945-8951.
[42]Honda R,Yasuda H.Activity of MDM2,a ubiquitin ligase,toward p53 or itself is dependent on the RING finger domain of the ligase.Oncogene,2000;19:1473-1476.
[43]Joazeiro CA,Wing SS,Huang H,et al.The tyrosine kinase negative regulator c-Cbl as a RING-type,E2-dependent ubiquitin-protein ligase.Science,1999;286:309-312.
[44]Waterman H,Levkowitz G,Alroy I,et al.The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor.J Biol Chem,1999;274:22151-22154.
[45]Ardley HC,Robinson PA.E3 ubiquitin ligases.Essays Biochem,2005;41:15-30.
[46]Ohta T,Michel JJ,Schottelius AJ,et al.ROCl,a homolog of APCll,represents a family of cullin partners with an associated ubiquitin ligase activity.Mol Cell,1999;3:535-541.
[47]Senl JH,Feldman RM,Zachariae W,et al.Cdc53/cullin and the essential Hrtl RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34.Genes Dev,1999;13:1614-1626.
[48]Skowyra D,Craig KL,Tyers M,et al.F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex.Cell,1997;91:209-219.
[49]Kamura T,Koepp DM,Conrad MN,et al.Rbxl,a component of the VHL tumor suppressor complex and SCF ubiquitin ligase.Science,1999;284:657-661.
[50]Lyapina SA,Correll CC,Kiprens ET,ct al.Human CUL1 forms an evolutionadly conserved ubiquitin ligase complex(SCF)with SKP1 and an F-box protein.Proe Natl Acad Sci U S A,1998;95:7451-7456.
[51]Carrano AC,Eytan E,Hershko A,et al.SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.Nat Cell Biol,1999;1:193-199.
[52]Montagnoli A,Fiore F,Eytan E,et al.Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.Genes Dev,1999;13:1181-1189.
[53]Nefsky B,Beach D.Publ acts as an E6-AP-like protein ubiquitiin ligase in the degradation of cdc25.EMBO J,1996;15:1301-1312.
[54]Willems AR,Goh T,Taylor L,et al.SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis.Philos Trans R Soe Load B Biol Sci,1999;354:1533-1550.
[55]Latres E,Chiaur DS,Pagano M.The human F box protein beta-Trcp associates with the Cull/Skp1 complex and regulates the stability of beta-catenin.Ondcogene,1999;18:849-854.
[56]Winston JT,Strack P,Beer-Romero P,et al.The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.Genes Dev,1999;13:270-283.
[57]Lonergan KM,Iliopoulos O,Ohh M,et al.Regulation of hypoxia-inducible mRNAs by the yon Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2.Mol Cell Biol,1998;18:732-741.
[58]Kamura T,Sato S,Haque D,et al.The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS,ras,WD-40 repeat,and ankyrin repeat families.Genes Dev,1998;12:3872-3881.
[59]Bruick RK,McKnight SL.A conserved family of prolyl-4-hydroxylases that modify HIF.Science,2001;294:1337-1340.
[60]Epstein AC,Gleadle JM,McNeill LA,et al.C.elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.Cell,2001;107:43 -54.
[61] Sudakin V, Ganoth D, Dahan A, et al. The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol Biol Cell, 1995;6:185-197.
[62] Passmore LA, Booth CR, Venien-Bryan C, et al. Structural analysis of the anaphase-promoting complex reveals multiple active sites and insights into polyubiquitylation. Mol Cell, 2005;20:855-866.
[63] Wasch R, Engelbert D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene, 2005;24:1-10.
[64] Vodermaier HC, Gieffers C, Maurer-Stroh S, et al. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1. Curr Biol, 2003;13:1459-1468.
[65] Passmore LA, McCormack EA, Au SW, et al. Docl mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. EMBO J, 2003;22:786-796.
[66] Cyr DM, Hohfeld J, Patterson C. Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem Sci, 2002;27:368-375.
[67] Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell, 1999;96:635-644.
[68] Hatakeyama S, Yada M, Matsumoto M, et al. U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem, 2001;276:33111-33120.
[69] Hatakeyama S, Matsumoto M, Kamura T, et al. U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy. J Neurochem, 2004;91:299-307.
[70] Shimura H, Schwartz D, Gygi SP, et al. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem, 2004;279:4869-4876.
[71] Nijman SM, Huang TT, Dirac AM, et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell, 2005;17:331-339.
[72] Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta, 2004; 1695:189-207.
[73] Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem, 1999;68:1015-1068.
[74] Hough R, Pratt G, Rechsteiner M. Ubiquitin-lysozyme conjugates. Identification and characterization of an ATP-dependent protease from rabbit reticulocyte lysates. J Biol Chem, 1986261:2400-2408.
[75] Arrigo AP, Tanaka K, Goldberg AL, et al. Identity of the 19S 'prosome' particle with the large multifunctional protease complex of mammalian cells (the proteasome). Nature, 1988;331:192-194.
[76] Fujiwara T, Tanaka K, Orino E, et al. Proteasomes are essential for yeast proliferation. cDNA cloning and gene disruption of two major subunits. J Biol Chem, 1990;265:16604-16613.
[77] Emori Y, Tsukahara T, Kawasaki H, et al. Molecular cloning and functional analysis of three subunits of yeast proteasome. Mol Cell Biol, 1991;11:344-353.
[78] Heinemeyer W, Kleinschmidt JA, Saidowsky J, et al. Proteinase yscE, the yeast proteasome/multicatalytic-multifunctional proteinase: mutants unravel its function in stress induced proteolysis and uncover its necessity for cell survival. EMBO J, 1991;10:555-562.
[79] Lowe J, Stock D, Jap B, et al. Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science, 1995;268:533-539.
[80] Peters JM, Franke WW, Kleinschmidt JA. Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. J Biol Chem, 1994;269:7709-7718.
[81] Ganoth D, Leshinsky E, Eytan E, et al. A multicomponent system that degrades proteins conjugated to ubiquitin. Resolution of factors and evidence for ATP-dependent complex formation. J Biol Chem, 1988;263:12412-12419.
[82] Groll M, Ditzel L, Lowe J, et al. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature, 1997;386:463-471.
[83] Wilk S, Orlowski M. Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex. J Neurochem, 1983;40:842-849.
[84] Groll M, Bajorek M, Kohler A, et al. A gated channel into the proteasome core particle. Nat Struct Biol, 2000;7:1062-1067.
[85] Wenzel T, Baumeister W. Conformational constraints in protein degradation by the 20S proteasome. Nat Struct Biol, 1995;2:199-204.
[86] Glickman MH, Rubin DM, Coux 0, et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell, 1998;94:615-623.
[87] Lupas A, Koster AJ, Baumeister W. Structural features of 26S and 20S proteasomes. Enzyme Protein, 1993;47:252-273.
[88] Larsen CN, Finley D. Protein translocation channels in the proteasome and other proteases. Cell, 1997;91:431-434.
[89] Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal. EMBO J,2000;19:94-102.
[90] Wenzel T, Eckerskom C, Lottspeich F, et al. Existence of a molecular ruler in proteasomes suggested by analysis of degradation products. FEBS Lett, 1994;349:205-209.
[91] d'Azzo A, Bongiovanni A, Nastasi T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic, 2005;6:429-441.
[92] Haglund K, Dikic I. Ubiquitylation and cell signaling. EMBO J, 2005;24:3353-3359.
[93] Sun L, Chen ZJ. The novel functions of ubiquitination in signaling. Curr Opin Cell Biol, 2004;16:119-126.
[94] Hofrnann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell, 1999;96:645-653.
[95] Huang TT, D'Andrea AD. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol, 2006;7:323-334.
[96] Adhikary S, Marinoni F, Hock A, et al. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell, 2005;123:409-421.
[97] Chen ZJ. Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol, 2005;7:758-765.
[98] Jura N, Scotto-Lavino E, Sobczyk A, et al. Differential modification of Ras proteins by ubiquitination. Mol Cell, 2006;21:679-687.
[99] Cadwell K, Coscoy L. Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science, 2005;309:127-130.
[100] Kirkpatrick DS, Hathaway NA, Hanna J, et al. Quantitative analysis of in vitro ubiquitinated cyclin Bl reveals complex chain topology. Nat Cell Biol, 2006;8:700-710.
[101] Attaix D, Aurousseau E, Combaret L, et al. Ubiquitin-proteasome-dependent proteolysis in skeletal muscle. Reprod Nutr Dev, 1998;38:153-165.
[102] Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med, 1996;335:1897-1905.
[103]Varshavsky A.The N-end rule:functions,mysteries,uses.Proe Natl Acad Sci U S A,1996;93:12142-12149.
[104]Bloom J,Amador V,Bartolini F,et al.Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation.Cell,2003;115:71-82.
[105]Turner GC,Du F,Varshavsky A.Peptides accelerate their uptake by activating a ubiquitin-dependent preteolytic pathway.Nature,2000;405:579-583.
[106]Tsvetkov LM,Yeh KH,Lee SJ,et al.p27(Kipl)ubiquitination and degradation is regulated by the SCF(Skp2)complex through phosphorylated Thr187 in p27.Curt Biol,1999;9:661-664.
[107]Sutterluty H,Chatelain E,Marti A,et al.p45SKP2 promotes p27Kipl degradation and induces S phase in quiescent cells.Nat Cell Biol,1999;1:207-214.
[108]Dimmeler S,Breitschopf K,Haendeler J,et al.Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation:a link between the apoptosome and the proteasome pathway.J Exp Med,1999;189:1815-1822.
[109]Kong SK,Chock PB.Protein ubiquitination is regulated by phosphorylation.An in vitro study.J Bioi Chem,1992;267:14189-14192.
[110]Ulrich HD.Mutual interactions between the SUMO and ubiquitin systems:a plea of no contest.Trends Cell Bioi,2005;15:525-532.
[111]Nakayama KI,Nakayama K.Ubiquitin ligases:cell-cycle control and cancer.Nat Rev Cancer,2006;6:369-381.
[112]Deshaies RJ.SCF and Cullin/Ring H2-based ubiquitin ligases.Annu Rev Cell Dev Biol,1999;15:435-467.
[113]Won KA,Reed SI.Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E.EMBO J,1996;15:4182-4193.
[114]Sheaff RJ,Groudine M,Gordon M,et al.Cyclin E-CDK2 is a regulator of p27Kipl.Genes Dev,1997;11:1464-1478.
[115]Harper JW,Burton JL,Solomon MJ.The anaphase-promoting complex:it's not just for mitosis any more.Genes Dev,2002;16:2179-2206.
[116]Castro A,Bemis C,Vigneron S,et al.The anaphase-promoting complex:a key factor in the regulation of cell cycle.Oncogene,2005;24:314-325.
[117]Guardavaccaro D,Kudo Y,Boulaire J,et al.Control of meiotic and mitotic progression by the F box protein beta-Trcpl in vivo.Dev Cell,2003;4:799-812.
[118]Margottin-Goguet F,Hsu JY,Loktev A,et al.Prophase destruction of Emil by the SCF(betaTrCP/Slimb)ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.Dev Cell,2003;4:813-826.
[119]Bashir T,Dorrello NV,Amador V,et al.Control of the SCF(Skp2-Cks1)ubiquitin ligase by the APC/C(Cdh1)ubiquitin ligase.Nature,2004;428:190-193.
[120]Wei W,Ayad NG,Wan Y,et al.Degradation of the SCF component Skp2 in cell-cycle phase Gl by the anaphase-promoting complex.Nature,2004;428:194-198.
[121]Nakayama K,Nagahama H,Minamishima YA,et al.Skp2-mediated degradation of p27regulates progression into mitosis.Dev Cell,2004;6:661-672.
[122]Zachariae W,Schwab M,Nasmyth K,et al.Control of cyclin ubiquitination by CDK-regulated binding of Hctl to the anaphase promoting complex.Science,1998;282:1721-1724.
[123]Jaspersen SL,Charles JF,Morgan DO.Inhibitory phosphorylation of the APC regulator Hctl is controlled by the kinase Cdc28 and the phosphatase Cdc14.Curr Biol,1999;9:227-236.
[124]Schwartz LM,Myer A,Kosz L,et al.Activation of polyubiquitin gene expression during developmentally programmed cell death.Neuron,1990;5:411-419.
[125]Yang Y,Fang S,Jensen JP,et al.Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.Science,2000;288:874-877.
[126]MacFarlane M,Merrison W,Bratton SB,et al.Proteasome-mediated degradation of Smac during apoptosis:XIAP promotes Smac ubiquitination in vitro.J Biol Chem,2002;277:36611-36616.
[127]Suzuki Y,Nakabayashi Y,Nakata K,et al.X-linked inhibitor of apoptosis protein(XIAP)inhibits caspase-3 and -7 in distinct modes.J Biol Chem,2001;276:27058-27063.
[128]Riedl SJ,Renatus M,Schwarzenbacher R,et al.Structural basis for the inhibition of caspase-3 by XIAP.Cell,2001;104:791-800.
[129]Breitschopf K,Zeiher AM,Dimmeler S.Ubiquitin-mediated degradation of the proapoptotic active form of bid.A functional consequence on apoptosis induction.J Biol Chem,2000;275:21648-21652.
[130]Li B,Dou QP.Bax degradation by the ubiquitin/proteasome-dependent pathway:involvement in tumor survival and progression.Proe Natl Acad Sci U S A,2000;97:3850-3855.
[131]Thomas M,Banks L.Inhibition of Bak-induced apoptosis by HPV-18 E6.Oneogene,1998;17:2943-2954.
[132]Burgers PM,Koonin EV,Bruford E,et al.Eukaryotic DNA polymerases:proposal for a revised nomenclature.J Bioi Chem,2001;276:43487-43490.
[133]Hoeller D,Hecker CM,Dikic I.Ubiquitin and ubiquitin-like proteins in cancer pathogenesis.Nat Rev Cancer,2006;6:776-788.
[134]Haracska L,Unk I,Johnson RE,et al.Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA.Mol Cell Biol,2002;22:784-791.
[135]Bailly V,Lauder S,Prakash S,et al.Yeast DNA repair proteins Rad6 and Rad18 form a heterodimer that has ubiquitin conjugating,DNA binding,and ATP hydrolytic activities.J Bioi Chem,1997;272:23360-23365.
[136]Friedberg EC,Lehmann AR,Fuchs RP.Trading places:how do DNA polymerases switch during translesion DNA synthesis? Mol Cell,2005;18:499-505.
[137]Kannouche PL,Wing J,Lehmann AR.Interaction of human DNA polymerase eta with monoubiquitinated PCNA:a possible mechanism for the polymerase switch in response to DNA damage.Mol Cell,2004;14:491-500.
[138]Haracska L,Unk I,Prakash L,et al.Ubiquitylation of yeast proliferating cell nuclear antigen and its implications for translesion DNA synthesis.Proe Natl Acad Sei U S A,2006;103:6477-6482.
[139]Brusky J,Zhu Y,Xiao W.UBC13,a DNA-damage-inducible gene,is a member of the error-flee postreplication repair pathway in Saccharomyces cerevisiae.Curr Genet,2000;37:168-174.
[140]Chiu RK,Brun J,Ramaekers C,et al.Lysine 63-polyubiquitination guards against translesion synthesis-induced mutations.PLoS Genet,2006;2:el16.
[141]Chen Z,Hagler J,Palombella VJ,et al.Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.Genes Dev,1995;9:1586-1597.
[142]Deng L,Wang C,Spencer E,et al.Activation of the IkappaB kinase complex by TRAF6requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.Cell,2000;103:351-361.
[143]Wang C,Deng L,Hong M,et al.TAK1 is a ubiquitin-dependent kinase of MKK and IKK.Nature.2001:412:346-351.
[144]Chen ZJ,Parent L,Maniatis T.Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity.Cell,1996;84:853-862.
[145]Spence J,Gali RR,Dittmar G,et al.Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain.Cell,2000;102:67-76.
[146]Tanowitz M,Von Zastrow M.Ubiquitination-independent trafficking of G protein-coupled receptors to lysosomes.J Bioi Chem,2002;277:50219-50222.
[147]Galan JM,Haguenauer-Tsapis R.Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein.EMBOJ,1997;16:5847-5854.
[148]Helliwell SB,Losko S,Kaiser CA.Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease.J Cell Biol,2001;153:649-662.
[149]Morvan J,Froissard M,Haguenauer-Tsapis R,et al.The ubiquitin ligase Rsp5p is required for modification and sorting of membrane proteins into multivesicular bodies.Traffic,2004;5:383-392.
[150]Sun ZW,Allis CD.Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.Nature,2002;418:104-108.
[151]Muratani M,Kung C,Shokat KM,et al.The F box protein Dsgl/Mdm30 is a transcriptional coactivator that stimulates Gal4 turnover and cotranscriptional mRNA processing.Cell,2005;120:887-899.
[152]Xirodimas DP,Saville MK,Bourdon JC,et al.Mdm2-mediated NEDD8 conjugation of p53inhibits its transcriptional activity.Cell,2004;118:83-97.
[153]Tenen DG.Disruption of differentiation in human cancer:AML shows the way.Nat Rev Cancer,2003;3:89-101.
[154]Diehl JA,Zindy F,Sherr CJ.Inhibition of cyclin D1 phosphorylation on threonine-286prevents its rapid degradation via the ubiquitin-proteasome pathway.Genes Dev,1997;11:957-972.
[155]Huang G,Shigesada K,Ito K,et al.Dimerization with PEBP2beta protects RUNX1/AML1from ubiquitin-proteasome-mediated degradation.EMBO J,2001;20:723-733.
[156]Minegishi N,Suzuki N,Kawatani Y,et al.Rapid tumover of GATA-2 via ubiquitin-proteasome protein degradation pathway.Genes Cells,2005;10:693-704.
[157]Shim M,Smart RC.Lithium stabilizes the CCAAT/enhancer-binding protein alpha (C/EBPalpha)through a glycogen synthase kinase 3(GSK3)-independent pathway involving direct inhibition of proteasomal activity.J Biol Chem,2003;278:19674-19681.
[158]Marteijn JA,van der Meer LT,Van Emst L,et al.Diminished proteasomal degradation results in accumulation of Gfil protein in m onocytes.Blood,2007;109:100-108.
[159]Marteijn JA,van Emst L,Erpelinck-Verschueren CA,et al.The E3 ubiquitin-protein ligase Triadl inhibits clonogenic growth of primary myeloid progenitor cells.Blood,2005;106:4114-4123.
[160]Chuang TH,Ulevitch RJ.Triad3A,an E3 ubiquitin-protein ligase regulating Toll-like receptors.Nat Immunol,2004;5:495-502.
[161]Li B,Yang FC,Clapp DW,et al.Enforced expression of CUL-4A interferes with granulocytie differentiation and exit from the cell cycle.Blood,2003;101:1769-1776.
[162]Zhang Y,Morrone G,Zhang J,et al.CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein.EMBO J,2003;22:6057-6067.
[163]Elliott J,Johnston JA.SOCS:role in inflammation,allergy and homeostasis.Trends Immunol,2004;25:434-440.
[164]Ungureanu D,Saharinen P,Junttila I,et al.Regulation of Jak2 through the ubiquitin-proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1.Mol Cell Biol,2002;22:3316-3326.
[165]Peschard P,Park M.Escape from Cbl-mediated downregulation:a recurrent theme for oncogenic deregulation of receptor tyrosine kinases.Cancer Cell,2003;3:519-523.
[166]Bache KG,Slagsvold T,Stenmark H.Defective downregulation of receptor tyrosine kinases in cancer.EMBO J,2004;23:2707-2712.
[167]Pagano M,Benmaamar R.When protein destruction runs amok,malignancy is on the loose.Cancer Cell,2003;4:251-256.
[168]Pastore Y,Jedlickova K,Guan Y,et al.Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.Am J Ham Genet,2003;73:412-419.
[169]D'Andrea AD,Grompe M.The Fanconi anaemia/BRCA pathway.Nat Rev Cancer,2003;3:23-34.
[170]Konikova E,Kusenda J.Altered expression of p53 and MDM2 proteins in hematological malignancies.Neoplasma,2003;50:31-40.
[171]Linggi B,Muller-Tidow C,van de Locht L,et al.The t(8;21)fusion protein,AML1 ETO,specifically represses the transcription of the p14(ARF)tumor suppressor in acute myeloid leukemia.Nat Med,2002;8:743-750.
[172]Pomerantz J,Schreiber-Agus N,Liegeois NJ,et al.The Ink4a tumor suppressor gene product,p19Arf,interacts with MDM2 and neutralizes MDM2's inhibition of p53.Cell,1998;92:713-723.
[173]Bahrain F,von der Lehr N,Cetinkaya C,et al.c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover.Blood,2000;95:2104-2110.
[174]Almond JB,Cohen GM.The proteasome:a novel target for cancer chemotherapy.Leukemia,2002;16:433-443.
[175]Spataro V,Norbury C,Harris AL.The ubiquitin-proteasome pathway in cancer.Br J Cancer,1998;77:448-455.
[176]Voorhees PM,Dees EC,O'Neil B,et al.The proteasome as a target for cancer therapy.Clin Cancer Res,2003;9:6316-6325.
[177]Wang CY,Mayo MW,Baldwin AS,Jr.TNF- and cancer therapy-induced apoptosis:potentiation by inhibition of NF-kappaB.Science,1996;274:784-787.
[178]Cusack JC,Jr.,Liu R,Houston M,et al.Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341:implications for systemic nuclear factor-kappaB inhibition.Cancer Res,2001;61:3535-3540.
[179]Russo SM,Tepper.JE,Baldwin AS,Jr.,et al.Enhancement of radiosensitivity by proteasome inhibition:implications for a role of NF-kappaB.Int J Radiat Oncol Biol Phys,2001;50:183-193.
[180]Vink J,Cloos J,Kaspers GJ.Proteasome inhibition as novel treatment strategy in leukaemia.Br J Haematol,2006;134:253-262.
[181]Hideshima T,Mitsiades C,Akiyama M,et al.Molecular mechanisms mediating antlmyeloma activity of proteasome inhibitor PS-341.Blood,2003;101:1530-1534.
[182]Mitsiades N,Mitsiades CS,Poulaki V,et al.Molecular sequelae of proteasome inhibition in human multiple myeloma cells.Proe Natl Acad Sci U S A,2002;99:14374-14379.
[183]Jung L,Holle L,Dalton WS.Discovery,Development,and clinical applications of bortezomib.Oneology(Williston Park),2004;18:4-13.
[184]Adams J.Development of the proteasome inhibitor PS-341.Oncologist,2002;7:9-16.
[185]Hideshima T,Chauhan D,Richardson P,et al.Identification and validation of novel therapeutic targets for multiple myeloma.J Clin Oncol,2005;23:6345-6350.
[186]Hideshima T,Richardson P,Chauhan D,et al.The proteasome inhibitor PS-341 inhibits growth,induces apoptosis,and overcomes drug resistance in human multiple myeloma cells.Cancer Res,2001;61:3071-3076.
[187]Chauhan D,Uchiyama H,Akbarali Y,et al.Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B.Blood,1996;87:1104-1112.
[188]Chauhan D,Pandey P,Hideshima T,et al.SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells.J Biol Chem,2000;275:27845-27850.
[189]Dankbar B,Padro T,Leo R,et al.Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.Blood,2000;95:2630-2636.
[190]Gupta D,Treon SP,Shima Y,et al.Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion:therapeutic applications.Leukemia,2001;15:1950-1961.
[191]Lichtenstein A,Tu Y,Fady C,et al.Interleukin-6 inhibits apoptosis of malignant plasma cells.Cell Immunol,1995;162:248-255.
[192]Hideshima T,Chauhan D,Richardson P,et al.NF-kappa B as a therapeutic target in multiple myeloma.J Biol Chem,2002;277:16639-16647.
[193]LeBlanc R,Catley LP,Hideshima T,et al.Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.Cancer Res,2002;62:4996-5000.
[194]Anderson KC.Targeted therapy for multiple myeloma.Semin Hematol,2001;38:286-294.
[195]Cavo M.Proteasome inhibitor bortezomib for the treatment of multiple myeloma.Leukemia,2006;20:1341-1352.
[196]Orlowski RZ,Stinchcombe TE,Mitchell BS,et al.Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.J Clin Oncol,2002;20:4420-4427.
[197]Richardson PG,Barlogie B,Berenson J,et al.A phase 2 study of bortezomib in relapsed,refractory myeloma.N Engl J Med,2003;348:2609-2617.
[198]Richardson PG,Sonneveld P,Schuster MW,et al.Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.N Engl J Med,2005;352:2487-2498.
[199]O'Connor OA,Wright J,Moskowitz C,et al.Phase Ⅱ clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.J Clin Oneol,2005;23:676-684.
[200]Goy A,Younes A,McLaughlin P,et al.Phase Ⅱ study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.J Clin Oncol,2005;23:667-675.
[201]Kumatori A,Tanaka K,Inamura N,et al.Abnormally high expression of proteasomes in human leukemic cells.Proc Natl Acad Sci U S A,1990;87:7071-7075.
[202]Shimbara N,Sato C,Takashima M,et al.Down-regulation of ubiquitin gene expression during differentiation of human leukemia cells.FEBS Lett,1993;322:235-239.
[203] Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood, 2001;98:2301-2307.
[204] Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood, 2003;101:3142-3149.
[205] Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A, 2002;99:16220-16225.
[206] Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res, 2004;10:3371-3376.
[207] Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood, 2005;105:3058-3065.
[208] Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res, 2003;9:1136-1144.
[209] Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood, 2003;101:2377-2380.
[210] Ling YH, Liebes L, Ng B, et al. PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther, 2002;l:841-849.
[211] Loo TW, Clarke DM. The human multidrug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy. FASEB J, 1999; 13:1724-1732.
[212] Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood, 2002;99:4525-4530.
[213] Small GW, Shi YY, Edmund NA, et al. Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol, 2004;66:1478-1490.
[214] Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol, 2005;129:755-762.
[215] Parcellier A, Gurbuxani S, Schmitt E, et al. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem Biophys Res Commun, 2003;304:505-512.
[216] Kawazoe Y, Nakai A, Tanabe M, et al. Proteasome inhibition leads to the activation of all members of the heat-shock-factor family. Eur J Biochem, 1998;255:356-362.
[217] Hideshima T, Podar K, Chauhan D, et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene, 2004;23:8766-8776.
[218] Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res, 2003;63:6174-6177.