PLK1在食管鳞状细胞癌中的表达变化及其作用机制研究
|
摘要
PLK1(Polo-like kinase 1)是调控中心体成熟、染色体分离和有丝分裂退出的丝氨酸/苏氨酸蛋白激酶。PLK1对于维持有丝分裂过程中基因组稳定性非常重要,在多种恶性肿瘤中发挥作用。我们实验室在前期工作中发现PLK1基因所在的16p12染色体区带在食管鳞癌中存在增益,本研究旨在探讨PLK1在食管鳞癌中的表达变化及其参与该病发生发展的分子机制。
我们首先采用免疫组化方法检测了PLK1在155例食管鳞癌中的表达及与肿瘤临床病理参数之间的关系,继而通过RNAi降低PLK1的表达,观察其对食管鳞癌细胞增殖、凋亡的影响,采用免疫共沉淀和激光共聚焦方法确定PLK1的相互作用蛋白。
结果表明,与相应的正常上皮相比,PLK1在71.6%的人食管鳞癌组织中表达明显升高。PLK1过表达与区域淋巴结转移(P=0.001)和肿瘤分期(P=0.033)密切相关。PLK1表达阳性患者的术后生存时间显著短于PLK1表达阴性的患者(P=0.001)。而且,多因素生存分析显示PLK1是一个独立的预后因素(RR=4.921,P=0.011)。通过荧光原位杂交(FISH)检测食管鳞癌中PLK1基因的扩增情况,发现37.5%的标本中包含PLK1基因的RP11-141E3位点发生了拷贝数的增加,说明基因扩增是PLK1在部分食管鳞癌组织中过表达的原因之一。
通过RNA干扰降低PLK1的表达,能显著抑制食管鳞癌细胞增殖,并诱导细胞发生凋亡。PI染色和流式细胞仪检测表明,与对照组相比PLK1-RNAi组出现明显的凋亡峰,并呈时间依赖性增强。抑制PLK1表达导致线粒体膜电位降低、caspase-9和caspase-3活化、以及下游多聚ADP核糖聚合酶(PARP)降解,同时表现线粒体凋亡通路相关蛋白Mcl-1和Bcl-2蛋白水平下降。免疫共沉淀和激光共聚焦分析结果显示PLK1在细胞内分别与survivin和α-catenin形成复合物。PLK1敲降导致survivin蛋白表达降低。
以上结果表明PLK1可能在细胞凋亡、分化、粘附和迁移中发挥作用。Survivin作为凋亡抑制蛋白,可能与PLK1的抗凋亡功能相关。PLK1可能是一个有应用价值的预后因子和潜在的食管鳞癌治疗靶点。
Polo-like kinase 1(PLK1) is one of the serine/threonine kinases involved in centrosome maturation,chromosome segregation and mitotic exit.PLK1 is frequently overexpressed in various kinds of human tumors.16p12 encompassing PLK1 gene has been previously identified as a common amplified region in esophageal squamous cell carcinoma(ESCC).The present study is to investigate the expression change of PLK1 in ESCC and the underlying molecular mechanisms through which PLK1 takes part in esophageal carcinogenesis and malignant development.
Immunohistochemistry in 155 ESCC and adjacent normal tissues showed that PLK1 expression was considerably increased in tumors compared with that in normal epithelia.PLK1 overexpression was significantly associated with regional lymph node metastasis(P=0.001) and tumor stage(P=0.033).The prognosis of patients with PLK1-positive tumors was significantly worse than that with PLK1-negative (P=0.001).Multivariate survival analysis showed that PLK1 was an independent prognostic factor(RP=4.921,P=0.011).Amplification of the locus RP11-141E3 containing PLK1 gene was observed in 37.5%of tumors by fluorescence in situ hybridization,suggesting that gene amplification was the mechanism underlying PLK1 overexpression in a part of esophageal carcinomas.
RNAi-mediated knockdown of PLK1 dramatically suppressed cell proliferation and resulted in apoptosis.Depletion of PLK1 activated the mitochondrial apoptotic pathway,which was substantiated by loss of mitochondrial membrane potential, reduction of survivin,Mcl-1 and Bcl-2,activation of caspase-9 and caspase-3 as well as cleavage of poly(ADP-ribose) polymerase(PARP).Co-immunoprecipitation and confocal microscopy displayed that PLK1 was associated with survivin andα-catenin.
These data suggest that PLK1 plays a part in adhesion,differentiation and migration of cells.Survivin is probably involved in anti-apoptotic function of PLK1. PLK1 might be a useful prognostic marker and a potential therapeutic target for ESCC.
我们首先采用免疫组化方法检测了PLK1在155例食管鳞癌中的表达及与肿瘤临床病理参数之间的关系,继而通过RNAi降低PLK1的表达,观察其对食管鳞癌细胞增殖、凋亡的影响,采用免疫共沉淀和激光共聚焦方法确定PLK1的相互作用蛋白。
结果表明,与相应的正常上皮相比,PLK1在71.6%的人食管鳞癌组织中表达明显升高。PLK1过表达与区域淋巴结转移(P=0.001)和肿瘤分期(P=0.033)密切相关。PLK1表达阳性患者的术后生存时间显著短于PLK1表达阴性的患者(P=0.001)。而且,多因素生存分析显示PLK1是一个独立的预后因素(RR=4.921,P=0.011)。通过荧光原位杂交(FISH)检测食管鳞癌中PLK1基因的扩增情况,发现37.5%的标本中包含PLK1基因的RP11-141E3位点发生了拷贝数的增加,说明基因扩增是PLK1在部分食管鳞癌组织中过表达的原因之一。
通过RNA干扰降低PLK1的表达,能显著抑制食管鳞癌细胞增殖,并诱导细胞发生凋亡。PI染色和流式细胞仪检测表明,与对照组相比PLK1-RNAi组出现明显的凋亡峰,并呈时间依赖性增强。抑制PLK1表达导致线粒体膜电位降低、caspase-9和caspase-3活化、以及下游多聚ADP核糖聚合酶(PARP)降解,同时表现线粒体凋亡通路相关蛋白Mcl-1和Bcl-2蛋白水平下降。免疫共沉淀和激光共聚焦分析结果显示PLK1在细胞内分别与survivin和α-catenin形成复合物。PLK1敲降导致survivin蛋白表达降低。
以上结果表明PLK1可能在细胞凋亡、分化、粘附和迁移中发挥作用。Survivin作为凋亡抑制蛋白,可能与PLK1的抗凋亡功能相关。PLK1可能是一个有应用价值的预后因子和潜在的食管鳞癌治疗靶点。
Polo-like kinase 1(PLK1) is one of the serine/threonine kinases involved in centrosome maturation,chromosome segregation and mitotic exit.PLK1 is frequently overexpressed in various kinds of human tumors.16p12 encompassing PLK1 gene has been previously identified as a common amplified region in esophageal squamous cell carcinoma(ESCC).The present study is to investigate the expression change of PLK1 in ESCC and the underlying molecular mechanisms through which PLK1 takes part in esophageal carcinogenesis and malignant development.
Immunohistochemistry in 155 ESCC and adjacent normal tissues showed that PLK1 expression was considerably increased in tumors compared with that in normal epithelia.PLK1 overexpression was significantly associated with regional lymph node metastasis(P=0.001) and tumor stage(P=0.033).The prognosis of patients with PLK1-positive tumors was significantly worse than that with PLK1-negative (P=0.001).Multivariate survival analysis showed that PLK1 was an independent prognostic factor(RP=4.921,P=0.011).Amplification of the locus RP11-141E3 containing PLK1 gene was observed in 37.5%of tumors by fluorescence in situ hybridization,suggesting that gene amplification was the mechanism underlying PLK1 overexpression in a part of esophageal carcinomas.
RNAi-mediated knockdown of PLK1 dramatically suppressed cell proliferation and resulted in apoptosis.Depletion of PLK1 activated the mitochondrial apoptotic pathway,which was substantiated by loss of mitochondrial membrane potential, reduction of survivin,Mcl-1 and Bcl-2,activation of caspase-9 and caspase-3 as well as cleavage of poly(ADP-ribose) polymerase(PARP).Co-immunoprecipitation and confocal microscopy displayed that PLK1 was associated with survivin andα-catenin.
These data suggest that PLK1 plays a part in adhesion,differentiation and migration of cells.Survivin is probably involved in anti-apoptotic function of PLK1. PLK1 might be a useful prognostic marker and a potential therapeutic target for ESCC.
引文
Adams,R.R.,Carmena,M.and Earnshaw,W.C.(2001).Chromosomal passengers and the (aurora)ABCs of mitosis.Trends Cell Biol 11,49-54.
Ando,K.,Ozaki,T.,Yamamoto,H.,Furuya,K.,Hosoda,M.,Hayashi,S.,Fukuzawa,M.and Nakagawara,A.(2004).Polo-like kinase 1(P1k1)inhibits p53 function by physical interaction and phosphorylation.J Biol Chem 279,25549-61.
Andrews,P.D.(2005).Aurora kinases:shining lights on the therapeutic horizon? Oncogene 24,5005-15.
Bahassi el,M.,Conn,C.W.,Myer,D.L.,Hennigan,R.R,McGowan,C.H.,Sanchez,Y.and Stambrook,P.J.(2002).Mammalian Polo-like kinase 3 (Plk3)is a multifunctional protein involved in stress response pathways.Oncogene 21,6633-40.
Beltrami,E.,Plescia,J.,Wilkinson,J.C,Duckett,C.S.and Altieri,D.C.(2004).Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis.J Biol Chem 279,2077-84.
Bishop,J.D.and Schumacher,J.M.(2002).Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP)by the Aurora B Kinase stimulates Aurora B kinase activity.J Biol Chem 277,27577-80.
Blanc-Brude,O.P.,Mesri,M.,Wall,N.R.,Plescia,J.,Dohi,T.and Altieri,D.C.(2003).Therapeutic targeting of the survivin pathway in cancer:initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis.Clin Cancer Res 9,2683-92.
Burns,T.R,Fei,P.,Scata,K.A.,Dicker,D.T.and El-Deiry,W.S.(2003).Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells.Mol Cell Biol 23,5556-71.
Casenghi,M.,Barr,F.A.and Nigg,E.A.(2005).Phosphorylation of Nip by Plkl negatively regulates its dynein-dynactin-dependent targeting to the centrosome.J Cell Sci 118,5101-8.
Chen,Y,Riley,D.J.,Zheng,L.,Chen,P.L.and Lee,W.H.(2002).Phosphorylation of the mitotic regulator protein Hecl by Nek2 kinase is essential for faithful chromosome segregation.J Biol Chem 277,49408-16.
Conn,C.W.,Hennigan,R.R,Dai,W,Sanchez,Y.and Stambrook,P.J.(2000).Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase,Plk3.Cancer Res 60,6826-31.
Dai,W,Li,Y.,Ouyang,B.,Pan,H.,Reissmann,P.,Li,J.,Wiest,J.,Stambrook,P.,Gluckman,J.L.,Noffsinger,A.et al.(2000).PRK,a cell cycle gene localized to 8p21,is downregulated in head and neck cancer.Genes Chromosomes Cancer 27,332-6.
Dai,W.,Liu,T.,Wang,Q.,Rao,C.V.and Reddy,B.S.(2002a).Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors.Int J Oncol 20,121-6.
Dai,W,Wang,Q.and Traganos,R (2002b).Polo-like kinases and centrosome regulation.Oncogene 21,6195-200.
De Luca,M.,Lavia,P.and Guarguaglini,G (2006).A functional interplay between Aurora-A,P1k1 and TPX2 at spindle poles:P1k1 controls centrosomal localization of Aurora-A and TPX2 spindle association.Cell Cycle 5,296-303.
Ditchfield,C,Johnson,V.L.,Tighe,A.,Ellston,R.,Haworth,C,Johnson,T.,Mortlock,A.,Keen,N.and Taylor,S.S.(2003).Aurora B couples chromosome alignment with anaphase by targeting BubRl,Mad2,and Cenp-E to kinetochores.J Cell Biol 161,267-80.
Donaldson,M.M.,Tavares,A.A.,Hagan,1.ML,Nigg,E.A.and Glover,D.M.(2001).The mitotic roles of Polo-like kinase.J Cell Sci 114,2357-8.
Du,J.and Harmon,G.J.(2002).The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor NM23-H1.Nucleic Acids Res 30,5465-75.
Elez,R.,Piiper,A.,Kronenberger,B.,Kock,M.,Brendel,M.,Hermann,E.,Pliquett,U.,Neumann,E.and Zeuzem,S.(2003).Tumor regression by combination antisense therapy against Plkl and Bcl-2.Oncogene 22,69-80.
Elia,A.E.,Rellos,P.,Haire,L.R,Chao,J.W.,Ivins,R J.,Hoepker,K.,Mohammad,D.,Cantley,L.C.,Smerdon,S.J.and Yaffe,M.B.(2003).The molecular basis for phosphodependent substrate targeting and regulation of P1ks by the Polo-box domain.Cell 115,83-95.
Ellinger-Ziegelbauer,H.,Karasuyama,H.,Yamada,E.,Tsujikawa,K.,Todokoro,K.and Nishida,E.(2000).Ste20-like kinase (SLK),a regulatory kinase for polo-like kinase (Plk)during the G2/M transition in somatic cells.Genes Cells 5,491-8.
Falck,J.,Mailand,N.,Syljuasen,R.G,Bartek,J.and Lukas,J.(2001).The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.Nature 410,842-7.
Fry,A.M.,Mayor,T.,Meraldi,P.,Stierhof,Y.D.,Tanaka,K.and Nigg,E.A.(1998).C-Napl,a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2.J Cell Biol 141,1563-74.
Gebhart,E.,Liehr,T.,Wolff,E.,Ries,J.,Fiedler,W.,Steininger,H.,Koscielny,S.and Girod,S.(1998).Pattern of genomic imbalances in oral squamous cell carcinomas with and without an increased copy number of 11q13.Int J Oncol 12,1151-5.
Giannini,A.L:,Vivanco,M.and Kypta,R.M.(2000a).alpha-catenin inhibits beta-catenin signaling by preventing formation of a beta-catenin*T-cell factor*DNA complex.J Biol Chem 275,21883-8.
Giannini,A.L.,Vivanco,M.M.and Kypta,R.M.(2000b).Analysis of beta-catenin aggregation and localization using GFP fusion proteins:nuclear import of alpha-catenin by the beta-catenin/Tcf complex.Exp Cell Res 255,207-20.
Goepfert,T.M.,Adigun,Y.E.,Zhong,L.,Gay,J.,Medina,D.and Brinkley,W.R.(2002).Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis.Cancer Res 62,4115-22.
Golan,A.,Yudkovsky,Y.and Hershko,A.(2002).The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and P1k.J Biol Chem 211,15552-7.
Golsteyn,R.M.,Mundt,K.E.,Fry,A.M.and Nigg,E.A.(1995).Cell cycle regulation of the activity and subcellular localization of P1k1,a human protein kinase implicated in mitotic spindle function.J Cell Biol 129,1617-28.
Grossman,D.,Kim,P.J.,Blanc-Brude,O.P.,Brash,D.E.,Tognin,S.,Marchisio,P.C.and Altieri,D.C.(2001).Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.J Clin Invest 108,991-9.
Guan,R.,Tapang,P.,Leverson,J.D.,Albert,D.,Giranda,V.L.and Luo,Y.(2005).Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective,oncogenic transformed cells and inhibits tumor growth in animals.Cancer Res 65,2698-704.
Gumireddy,K.,Reddy,M.V.,Cosenza,S.C.,Boominathan,R.,Baker,S.J.,Papathi,N.,Jiang,J.,Holland,J.and Reddy,E.P.(2005).ON01910,a non-ATP-competitive small molecule inhibitor of Plkl,is a potent anticancer agent.Cancer Cell 7,275-86.
Gunawardena,R.W.,Siddiqui,H.,Solomon,D.A.,Mayhew,C.N.,Held,J.,Angus,S.P.and Knudsen,E.S.(2004).Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plkl.J Biol Chem 279,29278-85.
Hansen,D.V.,Loktev,A.V.,Ban,K.H.and Jackson,P.K.(2004).Plkl regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emil.Mol Biol Cell 15,5623-34.
Harrington,E.A.,Bebbington,D.,Moore,J.,Rasmussen,R.K.,Ajose-Adeogun,A.O.,Nakayama,T.,Graham,J.A.,Demur,C.,Hercend,T.,Diu-Hercend,A.et al.(2004).VX-680,a potent and selective small-molecule inhibitor of the Aurora kinases,suppresses tumor growth in vivo.Nat Med 10,262-7.
Hashimoto,Y.,Ito,T.,Inoue,H.,Okumura,T.,Tanaka,E.,Tsunoda,S.,Higashiyama,M.,Watanabe,G,Imamura,M.and Shimada,Y.(2005).Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma.Clin Cancer Res 11,2597-605.
Hayward,D.G and Fry,A.M.(2005).Nek2 kinase in chromosome instability and cancer.Cancer Lett.
Hirota,T.,Kunitoku,N.,Sasayama,T.,Mammoto,T.,Zhang,D.,Nitta,M.,Hatakeyama,K.and Saya,H.(2003).Aurora-A and an interacting activator,the LIM protein Ajuba,are required for mitotic commitment in human cells.Cell 114,585-98.
Ikeguchi,M.,Oka,S.,Gomyo,Y,Tsujitani,S.,Maeta,M.and Kaibara,N.(2000).Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer.Ann Thorac Surg 70,913-7.
Ikeguchi,M.,Sakatani,T.,Ueta,T.and Kaibara,N.(2001).Cyclin Dl expression and retinoblastoma gene protein (pRB)expression in esophageal squamous cell carcinoma.J Cancer Res Clin Oncol 127,531-6.
Jackson,M.W.,Agarwal,M.K.,Yang,J.,Bruss,P.,Uchiumi,T.,Agarwal,M.L.,Stark,G R.and Taylor,W.R.(2005).p130/pl07/pl05Rb-dependent transcriptional repression during DNA-damage-induced cell-cycle exit at G2.J Cell Sci 118,1821-32.
Ji,J.H.and Jang,Y J.(2006).Screening of Domain-specific Target Proteins of Polo-like Kinase 1:Construction and Application of Centrosome/Kinetochore-specific Targeting Peptide.J Biochem Mol Biol 39,709-16.
Kadowaki,T.,Shiozaki,H.,Inoue,M.,Tamura,S.,Oka,H.,Doki,Y,Iihara,K.,Matsui,S.,Iwazawa,T.,Nagafuchi,A.et al.(1994).E-cadherin and alpha-catenin expression in human esophageal cancer.Cancer Res 54,291-6.
Kamada,K..Yamada,Y,Hirao,T.,Fujimoto,H.,Takahama,Y,Ueno,M.,Takayama,T.,Naito,A.,Hirao,S.and Nakajima,Y (2004).Amplification/overexpression of Aurora-A in human gastric carcinoma:potential role in differentiated type gastric carcinogenesis.Oncol Rep 12,593-9.
Kanaji,S.,Saito.H..Tsujitani,S.,Matsumoto,S.,Tatebe,S.,Kondo,A.,Ozaki,M.,Ito,H.and Ikeguchi,M.(2006).Expression of Polo-Like Kinase 1 (PLK1)Protein Predicts the Survival of Patients with Gastric Carcinoma.Oncology 70,126-133.
Kang,J.U.,Kang,J.J.,Kwon,K.C,Park,J.W.,Jeong,T.E.,Noh,S.M.and Koo,S.H.(2006).Genetic alterations in primary gastric carcinomas correlated with clinicopathological variables by array comparative genomic hybridization.J Korean Med Sci 21,656-65.
Katayama,H.,Brinkley,W.R.and Sen,S.(2003).The Aurora kinases:role in cell transformation and tumorigenesis.Cancer Metastasis Rev 22,451-64.
Katayama,H.,Ota,T.,Jisaki,R,Ueda,Y.,Tanaka,T.,Odashima,S.,Suzuki,R,Terada,Y.and Tatsuka,M.(1999).Mitotic kinase expression and colorectal cancer progression.J Natl Cancer Inst 91,1160-2.
Katayama,H.,Sasai,K.,Kawai,H.,Yuan,Z.M.,Bondaruk,J.,Suzuki,R,Fujii,S.,Arlinghaus,R.B.,Czerniak,B.A.and Sen,S.(2004).Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53.Nat Genet 36,55-62.
Katayama,H.,Zhou,H.,Li,Q.,Tatsuka,M.and Sen,S.(2001).Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle.J Biol Chem 276,46219-24.
Kawajiri,A.,Yasui,Y,Goto,H.,Tatsuka,M.,Takahashi,M.,Nagata,K.and Inagaki,M.(2003).Functional significance of the specific sites phosphorylated in desmin at cleavage furrow:Aurora-B may phosphorylate and regulate type Ⅲ intermediate filaments during cytokinesis coordinatedly with Rho-kinase.Mol Biol Cell 14,1489-500.
Knecht,R.,Elez,R.,Oechler,M.,Solbach,C,von Uberg,C.and Strebhardt,K.(1999).Prognostic significance of polo-like kinase (PLK)expression in squamous cell carcinomas of the head and neck.Cancer Res 59,2794-7.
Kunitoku,N.,Sasayama,T.,Marumoto,T.,Zhang,D.,Honda,S.,Kobayashi,O.,Hatakeyama,K.,Ushio,Y,Saya,H.and Hirota,T (2003).CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function.Dev Cell 5,853-64.
Kurasawa,Y,Earnshaw,W.C.,Mochizuki,Y,Dohmae,N.and Todokoro,K.(2004).Essential roles of KIF4 and its binding partner PRC1 in organized central spindle midzone formation.Embo J 23,3237-48.
Kuwano,H.,Kato,H.,Miyazaki,T.,Fukuchi,M.,Masuda,N.,Nakajima,M.,Fukai,Y.,Sohda,M.,Kimura,H.and Faried,A.(2005).Genetic alterations in esophageal cancer.Surg Today 35,7-18.
Lenart,P.,Petronczki,M.,Steegmaier,M.,Di Fiore,B.,Lipp,J.J.,Hoffmann,M.,Rettig,W.J.,Kraut,N.and Peters,J.M.(2007).The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1.Curr Biol 17,304-15.
Li,J.,Tan,M.,Li,L.,Pamarthy,D.,Lawrence,T.S.and Sun,Y (2005).SAK,a new polo-like kinase,is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing.Neoplasia 7,312-23.
Lin,H.R.,Ting,N.S.,Qin,J.and Lee,W.H.(2003).M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex.J Biol Chem 278,35979-87.
Lindon,C.and Pines,J.(2004).Ordered proteolysis in anaphase inactivates Plkl to contribute to proper mitotic exit in human cells.J Cell Biol 164,233-41.
Liu,Q.,Kaneko,S.,Yang,L.,Feldman,R.1.,Nicosia,S.V.,Chen,J.and Cheng,J.Q.(2004a).Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215.J Biol Chem 279,52175-82.
Liu,T.,Brouha,B.and Grossman,D.(2004b).Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells.Oncogene 23,39-48.
Liu,X.and Erikson,R.L.(2003).Polo-like kinase (Plk)I depletion induces apoptosis in cancer cells.Proc Natl Acad Sci U S A 100,5789-94.
Liu,X..Lei,M.and Erikson,R.L.(2006).Normal cells,but not cancer cells,survive severe plkl depletion.Mol Cell Biol 26,2093-108.
Liu,X.,Zhou,T.,Kuriyama,R.and Erikson,R.L.(2004c).Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHOl/MKLP-1.J Cell Sci 117,3233-46.
Manning,G,Whyte,D.B.,Martinez,R.,Hunter,T.and Sudarsanam,S.(2002).The protein kinase complement of the human genome.Science 298,1912-34.
Mesri,M,Wall,N.R.,Li,J.,Kim,R.W.and Altieri,D.C.(2001).Cancer gene therapy using a survivin mutant adenovirus.J Clin Invest 108,981-90.
Minoshima,Y.,Kawashima,T.,Hirose,K.,Tonozuka,Y,Kawajiri,A.,Bao,Y.C,Deng,X.,Tatsuka,M.,Narumiya,S.,May,W.S.,Jr.et al.(2003).Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis.Dev Cell 4,549-60.
Moshe,Y,Boulaire,J.,Pagano,M.and Hershko,A.(2004).Role of Polo-like kinase in the degradation of early mitotic inhibitor 1,a regulator of the anaphase promoting complex/cyclosome.Proc Natl Acad Sci U S A 101,7937-42.
Nakao,K.,Shibusawa,M.,Tsunoda,A.,Yoshizawa,H.,Murakami,M.,Kusano,M.,Uesugi,N.and Sasaki,K.(1998).Genetic changes in primary colorectal cancer by comparative genomic hybridization.Surg Today 28,567-9.
O'Connell,M.J.,Krien,M.J.and Hunter,T.(2003).Never say never.The NIMA-related protein kinases in mitotic control.Trends Cell Biol 13,221-8.
O'Connor,D.S.,Grossman,D.,Plescia,J.,Li,F.,Zhang,H.,Villa,A.,Tognin,S.,Marchisio,P.C.and Altieri,D.C.(2000).Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin.Proc Natl Acad Sci USA 97,13103-7.
O'Connor,D.S.,Wall,N.R.,Porter,A.C.and Altieri,D.C.(2002).A p34(cdc2)survival checkpoint in cancer.Cancer Cell 2,43-54.
Ouchi,M.,Fujiuchi,N.,Sasai,K.,Katayama,H.,Minamishima,Y A.,Ongusaha,P.P.,Deng,C,Sen,S.,Lee,S.W.and Ouchi,T.(2004).BRCA1 phosphorylation by Aurora-Ain the regulation of G2 to M transition.J Biol Chem 279,19643-8.
Perez-Moreno,M.and Fuchs,E.(2006).Catenins:keeping cells from getting their signals crossed.Dev Cell 11,601-12.
Rapley,J.,Baxter,J.E.,Blot,J.,Wattam,S.L.,Casenghi,M.,Meraldi,P.,Nigg,E.A.and Fry,A.M.(2005).Coordinate regulation of the mother centriole component nip by nek2 and plkl protein kinases.Mol Cell Biol 25,1309-24.
Reagan-Shaw,S.and Ahmad,N.(2005).Silencing of polo-like kinase (Plk)1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells:implications for the treatment of prostate cancer.Faseb J19,611-3.
Ree,A.H.,Bratland,A.,Nome,R.V.,Stokke,T.and Fodstad,O.(2003).Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1.Oncogene 22,8952-5.
Sasai,K.,Katayama,H.,Stenoien,D.L.,Fujii,S.,Honda,R.,Kimura,M.,Okano,Y,Tatsuka,M,Suzuki,F.,Nigg,E.A.et al.(2004).Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells.Cell Motil Cytoskeleton 59,249-63.
Sen,S.,Zhou,H.,Zhang,R.D.,Yoon,D.S.,Vakar-Lopez,F.,Ito,S.,Jiang,F.,Johnston,D.,Grossman,H.B.,Ruifrok,A.C.et al.(2002).Arnplification/overexpression of a mitotic kinase gene in human bladder cancer.J Natl Cancer Inst 94,1320-9.
Setoyama,T.,Natsugpe,S.,Okumura,H.,Matsumoto,M.,Uchikado,Y,Yokomakura,N.,Ishigami,S.and Aikou,T.(2007).alpha-catenin is a significant prognostic factor than E-cadherin in esophageal squamous cell carcinoma.J Surg Oncol 95,148-55.
Smith,M.R.,Wilson,M.L.,Hamanaka,R.,Chase,D.,Kung,H.,Longo,D.L.and Ferris,D.K.(1997).Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase.Biochem Biophys Res Commun 234,397-405.
Smits,V.A.,Klompmaker,R.,Arnaud,L.,Rijksen,G,Nigg,E.A.and Medema,R.H.(2000).Polo-like kinase-1 is a target of the DNA damage checkpoint.Nat Cell Biol 2,672-6.
Spankuch-Schmitt,B.,Bereiter-Hahn,J.,Kaufmann,M.and Strebhardt,K.(2002).Effect of RNA silencing of polo-like kinase-1 (PLK1)on apoptosis and spindle formation in human cancer cells.J Natl Cancer Inst 94,1863-77.
Spankuch,B.,Heim,S.,Kurunci-Csacsko,E.,Lindenau,C,Yuan,J.,Kaufmann,M.and Strebhardt,K.(2006).Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer Cells In vitro and In vivo.Cancer Res 66,5836-46.
Spankuch,B.,Matthess,Y.,Knecht,R.,Zimmer,B.,Kaufmann,M.and Strebhardt,K.(2004).Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1.J Natl Cancer Inst 96,862-72.
Steegmaier,M.,Hoffmann,M.,Baum,A.,Lenart,R,Petronczki,M.,Krssak,M.,Gurtler,U.,Garin-Chesa,P.,Lieb,S.,Quant,J.et al.(2007).BI 2536,a potent and selective inhibitor of polo-like kinase 1,inhibits tumor growth in vivo.Curr Biol 17,316-22.
Stenoien,D.L.,Sen,S.,Mancini,M.A.and Brinkley,B.R.(2003).Dynamic association of a tumor amplified kinase,Aurora-A,with the centrosome and mitotic spindle.Cell Motil Cytoskeleton 55,134-46.
Stevenson,C.S.,Capper,E.A.,Roshak,A.K.,Marquez,B.,Eichman,C,Jackson,J.R.,Mattern,M.,Gerwick,W.H.,Jacobs,R.S.and Marshall,L.A.(2002).The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore.J Pharmacol Exp Ther 303,858-66.
Strebhardt,K.and Ullrich,A.(2006).Targeting polo-like kinase 1 for cancer therapy.Nat Rev Cancer 6,321-30.
Sugiyama,K.,Sugiura,K.,Hara,T.,Sugimoto,K.,Shima,H.,Honda,K.,Furukawa,K.,Yamashita,S.and Urano,T.(2002).Aurora-B associated protein phosphatases as negative regulators of kinase activation.Oncogene 21,3103-11.
Sumara,I.,Vorlaufer,E.,Stukenberg,P.T.,Kelm,O.,Redemann,N.,Nigg,E.A.and Peters,J.M.(2002).The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase.Mol Cell 9,515-25.
Sunkel,C.E.and Glover,D.M.(1988).polo,a mitotic mutant of Drosophila displaying abnormal spindle poles.J Cell Sci 89 (Pt 1),25-38.
Swallow,C.J.,Ko,M.A.,Siddiqui,N.U.,Hudson,J.W.and Dennis,J.W.(2005).Sak/Plk4 and mitotic fidelity.Oncogene 24,306-12.
Takahashi,T.,Sano,B.,Nagata,T,Kato,H.,Sugiyama,Y,Kunieda,K.,Kimura,M.,Okano,Y and Saji,S.(2003).Polo-like kinase 1 (PLK1)is overexpressed in primary colorectal cancers.Cancer Sci 94,148-52.
Takai,N.,Hamanaka,R.,Yoshimatsu,J.and Miyakawa,I.(2005).Polo-like kinases (P1ks)and cancer.Oncogene 24,287-91.
Tirkkonen,M.,Tanner,M.,Karhu,R.,Kallioniemi,A.,Isola,J.and Kallioniemi,O.P.(1998).Molecular cytogenetics of primary breast cancer by CGH.Genes Chromosomes Cancer 21,177-84.
Tong,T.,Zhong,Y.,Kong,J.,Dong,L.,Song,Y,Fu,M.,Liu,Z.,Wang,M.,Guo,L.,Lu,S.et al.(2004).Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma.Clin Cancer Res 10,7304-10.
Toyoshima-Morimoto,F.,Taniguchi,E.and Nishida,E.(2002).Plkl promotes nuclear translocation of human Cdc25C during prophase.EMBO Rep 3,341-8.
Toyoshima-Morimoto,F.,Taniguchi,E.,Shinya,N.,Iwamatsu,A.and Nishida,E.(2001).Polo-like kinase 1 phosphorylates cyclin Bl and targets it to the nucleus during prophase.Nature 410,215-20.
Tsvetkov,L.,Xu,X.,Li,J.and Stern,D.F.(2003).Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody.J Biol Chem 278,8468-75.
Wall,N.R.,O'Connor,D.S.,Plescia,J.,Pommier,Y and Altieri,D.C.(2003).Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.Cancer Res 63,230-5.
Warnke,S.,Kemmler,S.,Hames,R.S.,Tsai,H.L.,Hoffmann-Rohrer,U.,Fry,A.M.and Hoffmann,I.(2004).Polo-like kinase-2 is required for centriole duplication in mammalian cells.Curr Biol 14,1200-7.
Wei,F.,Ni,J.,Wu,S.S.,Liu,H.,Xu,X.,Han,Y L.,Cai,Y,Zhang,J.W.,Chen,X.J.,Pang,H.et al.(2002).Cytogenetic studies of esophageal squamous cell carcinomas in the northern Chinese population by comparative genomic hybridization.Cancer Genet Cytogenet 138,38-43.
Weichert,W.,Denkert,C,Schmidt,M.,Gekeler,V.,Wolf,G,Kobel,M.,Dietel,M.and Hauptmann,S.(2004a).Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma.Br J Cancer 90,815-21.
Weichert,W.,Kristiansen,G,Schmidt,M.,Gekeler,V.,Noske,A.,Niesporek,S.,Dietel,M.and Denkert,C.(2005a).Polo-like kinase 1 expression is a prognostic factor in human colon cancer.World J Gastroenterol 11,5644-50.
Weichert,W.,Kristiansen,G,Winzer,K.J.,Schmidt,M.,Gekeler,V.,Noske,A.,Muller,B.M,Niesporek,S.,Dietel,M.and Denkert,C.(2005b).Polo-like kinase isoforms in breast cancer:expression patterns and prognostic implications.Virchows Arch 446,442-50.
Weichert,W.,Schmidt,M.,Gekeler,V.,Denkert,C,Stephan,C,Jung,K.,Loening,S.,Dietel,M.and Kristiansen,G.(2004b).Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades.Prostate 60,240-5.
Wolf,G,Elez,R.,Doermer,A.,Holtrich,U.,Ackermann,H.,Stutte,H.J.,Altmannsberger,H.M.,Rubsamen-Waigmartn,H.and Strebhardt,K.(1997).Prognostic significance of polo-like kinase (PLK)expression in non-small cell lung cancer.Oncogene 14,543-9.
Xie,S.,Wu,H.,Wang,Q.,Cogswell,J.P.,Husain,I.,Conn,C,Stambrook,P.,Jhanwar-Uniyal,M.and Dai,W.(2001).Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.J Biol Chem 276,43305-12.
Yamamoto,Y,Matsuyama,H.,Kawauchi,S.,Matsumoto,H.,Nagao,K.,Ohmi,C,Sakano,S.,Furuya,T.,Oga,A.,Naito,K.et al.(2006).Overexpression of Polo-Like Kinase 1 (PLK1)and Chromosomal Instability in Bladder Cancer.Oncology 70,231-237.
Yarm,F.R.(2002).Plk phosphorylation regulates the microtubule-stabilizing protein TCTP.Mol Cell Biol 22,6209-21.
Yu,X.,Minter-Dykhouse,K.,Malureanu,L.,Zhao,W.M.,Zhang,D.,Merkle,C.J.,Ward,I.M.,Saya,H.,Fang,G,van Deursen,J.et al.(2005).Chfr is required for tumor suppression and Aurora A regulation.Nat Genet 37,401-6.
Yuan,J.,Eckerdt,F.,Bereiter-Hahn,J.,Kurunci-Csacsko,E.,Kaufmann,M.and Strebhardt,K.(2002).Cooperative phosphorylation including the activity of
polo-like kinase 1 regulates the subcellular localization of cyclin B1.Oncogene 21,8282-92.
Zhou,H.,Kuang,J.,Zhong,L.,Kuo,W.L.,Gray,J.W.,Sahin,A.,Brinkley,B.R.and Sen,S.(1998).Tumour amplified kinase STK15/BTAK induces centrosome amplification,aneuploidy and transformation.Nat Genet 20,189-93.
Zhou,J.,O'Brate,A.,Zelnak,A.and Giarmakakou,P.(2004).Survivin deregulation in beta-tubulin mutant ovarian cancer cells-underlies their compromised mitotic response to taxol.Cancer Res 64,8708-14.
Zimmerman,W.C.and Erikson,R.L.(2007).Polo-like kinase 3 is required for entry into S phase.Proc Natl Acad Sci U S A 104,1847-52.
韩亚玲,魏芳,徐昕,蔡岩,陈宝生,王洁,夏书华,胡海,黄晓平,汉雨生et al.(2002).人食管鳞癌细胞系EC9706的建立及其比较基因组杂交分析.中华医学遗传学杂志19,455-7.
Ando,K.,Ozaki,T.,Yamamoto,H.,Furuya,K.,Hosoda,M.,Hayashi,S.,Fukuzawa,M.and Nakagawara,A.(2004).Polo-like kinase 1(P1k1)inhibits p53 function by physical interaction and phosphorylation.J Biol Chem 279,25549-61.
Andrews,P.D.(2005).Aurora kinases:shining lights on the therapeutic horizon? Oncogene 24,5005-15.
Bahassi el,M.,Conn,C.W.,Myer,D.L.,Hennigan,R.R,McGowan,C.H.,Sanchez,Y.and Stambrook,P.J.(2002).Mammalian Polo-like kinase 3 (Plk3)is a multifunctional protein involved in stress response pathways.Oncogene 21,6633-40.
Beltrami,E.,Plescia,J.,Wilkinson,J.C,Duckett,C.S.and Altieri,D.C.(2004).Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis.J Biol Chem 279,2077-84.
Bishop,J.D.and Schumacher,J.M.(2002).Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP)by the Aurora B Kinase stimulates Aurora B kinase activity.J Biol Chem 277,27577-80.
Blanc-Brude,O.P.,Mesri,M.,Wall,N.R.,Plescia,J.,Dohi,T.and Altieri,D.C.(2003).Therapeutic targeting of the survivin pathway in cancer:initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis.Clin Cancer Res 9,2683-92.
Burns,T.R,Fei,P.,Scata,K.A.,Dicker,D.T.and El-Deiry,W.S.(2003).Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells.Mol Cell Biol 23,5556-71.
Casenghi,M.,Barr,F.A.and Nigg,E.A.(2005).Phosphorylation of Nip by Plkl negatively regulates its dynein-dynactin-dependent targeting to the centrosome.J Cell Sci 118,5101-8.
Chen,Y,Riley,D.J.,Zheng,L.,Chen,P.L.and Lee,W.H.(2002).Phosphorylation of the mitotic regulator protein Hecl by Nek2 kinase is essential for faithful chromosome segregation.J Biol Chem 277,49408-16.
Conn,C.W.,Hennigan,R.R,Dai,W,Sanchez,Y.and Stambrook,P.J.(2000).Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase,Plk3.Cancer Res 60,6826-31.
Dai,W,Li,Y.,Ouyang,B.,Pan,H.,Reissmann,P.,Li,J.,Wiest,J.,Stambrook,P.,Gluckman,J.L.,Noffsinger,A.et al.(2000).PRK,a cell cycle gene localized to 8p21,is downregulated in head and neck cancer.Genes Chromosomes Cancer 27,332-6.
Dai,W.,Liu,T.,Wang,Q.,Rao,C.V.and Reddy,B.S.(2002a).Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors.Int J Oncol 20,121-6.
Dai,W,Wang,Q.and Traganos,R (2002b).Polo-like kinases and centrosome regulation.Oncogene 21,6195-200.
De Luca,M.,Lavia,P.and Guarguaglini,G (2006).A functional interplay between Aurora-A,P1k1 and TPX2 at spindle poles:P1k1 controls centrosomal localization of Aurora-A and TPX2 spindle association.Cell Cycle 5,296-303.
Ditchfield,C,Johnson,V.L.,Tighe,A.,Ellston,R.,Haworth,C,Johnson,T.,Mortlock,A.,Keen,N.and Taylor,S.S.(2003).Aurora B couples chromosome alignment with anaphase by targeting BubRl,Mad2,and Cenp-E to kinetochores.J Cell Biol 161,267-80.
Donaldson,M.M.,Tavares,A.A.,Hagan,1.ML,Nigg,E.A.and Glover,D.M.(2001).The mitotic roles of Polo-like kinase.J Cell Sci 114,2357-8.
Du,J.and Harmon,G.J.(2002).The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor NM23-H1.Nucleic Acids Res 30,5465-75.
Elez,R.,Piiper,A.,Kronenberger,B.,Kock,M.,Brendel,M.,Hermann,E.,Pliquett,U.,Neumann,E.and Zeuzem,S.(2003).Tumor regression by combination antisense therapy against Plkl and Bcl-2.Oncogene 22,69-80.
Elia,A.E.,Rellos,P.,Haire,L.R,Chao,J.W.,Ivins,R J.,Hoepker,K.,Mohammad,D.,Cantley,L.C.,Smerdon,S.J.and Yaffe,M.B.(2003).The molecular basis for phosphodependent substrate targeting and regulation of P1ks by the Polo-box domain.Cell 115,83-95.
Ellinger-Ziegelbauer,H.,Karasuyama,H.,Yamada,E.,Tsujikawa,K.,Todokoro,K.and Nishida,E.(2000).Ste20-like kinase (SLK),a regulatory kinase for polo-like kinase (Plk)during the G2/M transition in somatic cells.Genes Cells 5,491-8.
Falck,J.,Mailand,N.,Syljuasen,R.G,Bartek,J.and Lukas,J.(2001).The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.Nature 410,842-7.
Fry,A.M.,Mayor,T.,Meraldi,P.,Stierhof,Y.D.,Tanaka,K.and Nigg,E.A.(1998).C-Napl,a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2.J Cell Biol 141,1563-74.
Gebhart,E.,Liehr,T.,Wolff,E.,Ries,J.,Fiedler,W.,Steininger,H.,Koscielny,S.and Girod,S.(1998).Pattern of genomic imbalances in oral squamous cell carcinomas with and without an increased copy number of 11q13.Int J Oncol 12,1151-5.
Giannini,A.L:,Vivanco,M.and Kypta,R.M.(2000a).alpha-catenin inhibits beta-catenin signaling by preventing formation of a beta-catenin*T-cell factor*DNA complex.J Biol Chem 275,21883-8.
Giannini,A.L.,Vivanco,M.M.and Kypta,R.M.(2000b).Analysis of beta-catenin aggregation and localization using GFP fusion proteins:nuclear import of alpha-catenin by the beta-catenin/Tcf complex.Exp Cell Res 255,207-20.
Goepfert,T.M.,Adigun,Y.E.,Zhong,L.,Gay,J.,Medina,D.and Brinkley,W.R.(2002).Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis.Cancer Res 62,4115-22.
Golan,A.,Yudkovsky,Y.and Hershko,A.(2002).The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and P1k.J Biol Chem 211,15552-7.
Golsteyn,R.M.,Mundt,K.E.,Fry,A.M.and Nigg,E.A.(1995).Cell cycle regulation of the activity and subcellular localization of P1k1,a human protein kinase implicated in mitotic spindle function.J Cell Biol 129,1617-28.
Grossman,D.,Kim,P.J.,Blanc-Brude,O.P.,Brash,D.E.,Tognin,S.,Marchisio,P.C.and Altieri,D.C.(2001).Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.J Clin Invest 108,991-9.
Guan,R.,Tapang,P.,Leverson,J.D.,Albert,D.,Giranda,V.L.and Luo,Y.(2005).Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective,oncogenic transformed cells and inhibits tumor growth in animals.Cancer Res 65,2698-704.
Gumireddy,K.,Reddy,M.V.,Cosenza,S.C.,Boominathan,R.,Baker,S.J.,Papathi,N.,Jiang,J.,Holland,J.and Reddy,E.P.(2005).ON01910,a non-ATP-competitive small molecule inhibitor of Plkl,is a potent anticancer agent.Cancer Cell 7,275-86.
Gunawardena,R.W.,Siddiqui,H.,Solomon,D.A.,Mayhew,C.N.,Held,J.,Angus,S.P.and Knudsen,E.S.(2004).Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plkl.J Biol Chem 279,29278-85.
Hansen,D.V.,Loktev,A.V.,Ban,K.H.and Jackson,P.K.(2004).Plkl regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emil.Mol Biol Cell 15,5623-34.
Harrington,E.A.,Bebbington,D.,Moore,J.,Rasmussen,R.K.,Ajose-Adeogun,A.O.,Nakayama,T.,Graham,J.A.,Demur,C.,Hercend,T.,Diu-Hercend,A.et al.(2004).VX-680,a potent and selective small-molecule inhibitor of the Aurora kinases,suppresses tumor growth in vivo.Nat Med 10,262-7.
Hashimoto,Y.,Ito,T.,Inoue,H.,Okumura,T.,Tanaka,E.,Tsunoda,S.,Higashiyama,M.,Watanabe,G,Imamura,M.and Shimada,Y.(2005).Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma.Clin Cancer Res 11,2597-605.
Hayward,D.G and Fry,A.M.(2005).Nek2 kinase in chromosome instability and cancer.Cancer Lett.
Hirota,T.,Kunitoku,N.,Sasayama,T.,Mammoto,T.,Zhang,D.,Nitta,M.,Hatakeyama,K.and Saya,H.(2003).Aurora-A and an interacting activator,the LIM protein Ajuba,are required for mitotic commitment in human cells.Cell 114,585-98.
Ikeguchi,M.,Oka,S.,Gomyo,Y,Tsujitani,S.,Maeta,M.and Kaibara,N.(2000).Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer.Ann Thorac Surg 70,913-7.
Ikeguchi,M.,Sakatani,T.,Ueta,T.and Kaibara,N.(2001).Cyclin Dl expression and retinoblastoma gene protein (pRB)expression in esophageal squamous cell carcinoma.J Cancer Res Clin Oncol 127,531-6.
Jackson,M.W.,Agarwal,M.K.,Yang,J.,Bruss,P.,Uchiumi,T.,Agarwal,M.L.,Stark,G R.and Taylor,W.R.(2005).p130/pl07/pl05Rb-dependent transcriptional repression during DNA-damage-induced cell-cycle exit at G2.J Cell Sci 118,1821-32.
Ji,J.H.and Jang,Y J.(2006).Screening of Domain-specific Target Proteins of Polo-like Kinase 1:Construction and Application of Centrosome/Kinetochore-specific Targeting Peptide.J Biochem Mol Biol 39,709-16.
Kadowaki,T.,Shiozaki,H.,Inoue,M.,Tamura,S.,Oka,H.,Doki,Y,Iihara,K.,Matsui,S.,Iwazawa,T.,Nagafuchi,A.et al.(1994).E-cadherin and alpha-catenin expression in human esophageal cancer.Cancer Res 54,291-6.
Kamada,K..Yamada,Y,Hirao,T.,Fujimoto,H.,Takahama,Y,Ueno,M.,Takayama,T.,Naito,A.,Hirao,S.and Nakajima,Y (2004).Amplification/overexpression of Aurora-A in human gastric carcinoma:potential role in differentiated type gastric carcinogenesis.Oncol Rep 12,593-9.
Kanaji,S.,Saito.H..Tsujitani,S.,Matsumoto,S.,Tatebe,S.,Kondo,A.,Ozaki,M.,Ito,H.and Ikeguchi,M.(2006).Expression of Polo-Like Kinase 1 (PLK1)Protein Predicts the Survival of Patients with Gastric Carcinoma.Oncology 70,126-133.
Kang,J.U.,Kang,J.J.,Kwon,K.C,Park,J.W.,Jeong,T.E.,Noh,S.M.and Koo,S.H.(2006).Genetic alterations in primary gastric carcinomas correlated with clinicopathological variables by array comparative genomic hybridization.J Korean Med Sci 21,656-65.
Katayama,H.,Brinkley,W.R.and Sen,S.(2003).The Aurora kinases:role in cell transformation and tumorigenesis.Cancer Metastasis Rev 22,451-64.
Katayama,H.,Ota,T.,Jisaki,R,Ueda,Y.,Tanaka,T.,Odashima,S.,Suzuki,R,Terada,Y.and Tatsuka,M.(1999).Mitotic kinase expression and colorectal cancer progression.J Natl Cancer Inst 91,1160-2.
Katayama,H.,Sasai,K.,Kawai,H.,Yuan,Z.M.,Bondaruk,J.,Suzuki,R,Fujii,S.,Arlinghaus,R.B.,Czerniak,B.A.and Sen,S.(2004).Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53.Nat Genet 36,55-62.
Katayama,H.,Zhou,H.,Li,Q.,Tatsuka,M.and Sen,S.(2001).Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle.J Biol Chem 276,46219-24.
Kawajiri,A.,Yasui,Y,Goto,H.,Tatsuka,M.,Takahashi,M.,Nagata,K.and Inagaki,M.(2003).Functional significance of the specific sites phosphorylated in desmin at cleavage furrow:Aurora-B may phosphorylate and regulate type Ⅲ intermediate filaments during cytokinesis coordinatedly with Rho-kinase.Mol Biol Cell 14,1489-500.
Knecht,R.,Elez,R.,Oechler,M.,Solbach,C,von Uberg,C.and Strebhardt,K.(1999).Prognostic significance of polo-like kinase (PLK)expression in squamous cell carcinomas of the head and neck.Cancer Res 59,2794-7.
Kunitoku,N.,Sasayama,T.,Marumoto,T.,Zhang,D.,Honda,S.,Kobayashi,O.,Hatakeyama,K.,Ushio,Y,Saya,H.and Hirota,T (2003).CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function.Dev Cell 5,853-64.
Kurasawa,Y,Earnshaw,W.C.,Mochizuki,Y,Dohmae,N.and Todokoro,K.(2004).Essential roles of KIF4 and its binding partner PRC1 in organized central spindle midzone formation.Embo J 23,3237-48.
Kuwano,H.,Kato,H.,Miyazaki,T.,Fukuchi,M.,Masuda,N.,Nakajima,M.,Fukai,Y.,Sohda,M.,Kimura,H.and Faried,A.(2005).Genetic alterations in esophageal cancer.Surg Today 35,7-18.
Lenart,P.,Petronczki,M.,Steegmaier,M.,Di Fiore,B.,Lipp,J.J.,Hoffmann,M.,Rettig,W.J.,Kraut,N.and Peters,J.M.(2007).The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1.Curr Biol 17,304-15.
Li,J.,Tan,M.,Li,L.,Pamarthy,D.,Lawrence,T.S.and Sun,Y (2005).SAK,a new polo-like kinase,is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing.Neoplasia 7,312-23.
Lin,H.R.,Ting,N.S.,Qin,J.and Lee,W.H.(2003).M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex.J Biol Chem 278,35979-87.
Lindon,C.and Pines,J.(2004).Ordered proteolysis in anaphase inactivates Plkl to contribute to proper mitotic exit in human cells.J Cell Biol 164,233-41.
Liu,Q.,Kaneko,S.,Yang,L.,Feldman,R.1.,Nicosia,S.V.,Chen,J.and Cheng,J.Q.(2004a).Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215.J Biol Chem 279,52175-82.
Liu,T.,Brouha,B.and Grossman,D.(2004b).Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells.Oncogene 23,39-48.
Liu,X.and Erikson,R.L.(2003).Polo-like kinase (Plk)I depletion induces apoptosis in cancer cells.Proc Natl Acad Sci U S A 100,5789-94.
Liu,X..Lei,M.and Erikson,R.L.(2006).Normal cells,but not cancer cells,survive severe plkl depletion.Mol Cell Biol 26,2093-108.
Liu,X.,Zhou,T.,Kuriyama,R.and Erikson,R.L.(2004c).Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHOl/MKLP-1.J Cell Sci 117,3233-46.
Manning,G,Whyte,D.B.,Martinez,R.,Hunter,T.and Sudarsanam,S.(2002).The protein kinase complement of the human genome.Science 298,1912-34.
Mesri,M,Wall,N.R.,Li,J.,Kim,R.W.and Altieri,D.C.(2001).Cancer gene therapy using a survivin mutant adenovirus.J Clin Invest 108,981-90.
Minoshima,Y.,Kawashima,T.,Hirose,K.,Tonozuka,Y,Kawajiri,A.,Bao,Y.C,Deng,X.,Tatsuka,M.,Narumiya,S.,May,W.S.,Jr.et al.(2003).Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis.Dev Cell 4,549-60.
Moshe,Y,Boulaire,J.,Pagano,M.and Hershko,A.(2004).Role of Polo-like kinase in the degradation of early mitotic inhibitor 1,a regulator of the anaphase promoting complex/cyclosome.Proc Natl Acad Sci U S A 101,7937-42.
Nakao,K.,Shibusawa,M.,Tsunoda,A.,Yoshizawa,H.,Murakami,M.,Kusano,M.,Uesugi,N.and Sasaki,K.(1998).Genetic changes in primary colorectal cancer by comparative genomic hybridization.Surg Today 28,567-9.
O'Connell,M.J.,Krien,M.J.and Hunter,T.(2003).Never say never.The NIMA-related protein kinases in mitotic control.Trends Cell Biol 13,221-8.
O'Connor,D.S.,Grossman,D.,Plescia,J.,Li,F.,Zhang,H.,Villa,A.,Tognin,S.,Marchisio,P.C.and Altieri,D.C.(2000).Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin.Proc Natl Acad Sci USA 97,13103-7.
O'Connor,D.S.,Wall,N.R.,Porter,A.C.and Altieri,D.C.(2002).A p34(cdc2)survival checkpoint in cancer.Cancer Cell 2,43-54.
Ouchi,M.,Fujiuchi,N.,Sasai,K.,Katayama,H.,Minamishima,Y A.,Ongusaha,P.P.,Deng,C,Sen,S.,Lee,S.W.and Ouchi,T.(2004).BRCA1 phosphorylation by Aurora-Ain the regulation of G2 to M transition.J Biol Chem 279,19643-8.
Perez-Moreno,M.and Fuchs,E.(2006).Catenins:keeping cells from getting their signals crossed.Dev Cell 11,601-12.
Rapley,J.,Baxter,J.E.,Blot,J.,Wattam,S.L.,Casenghi,M.,Meraldi,P.,Nigg,E.A.and Fry,A.M.(2005).Coordinate regulation of the mother centriole component nip by nek2 and plkl protein kinases.Mol Cell Biol 25,1309-24.
Reagan-Shaw,S.and Ahmad,N.(2005).Silencing of polo-like kinase (Plk)1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells:implications for the treatment of prostate cancer.Faseb J19,611-3.
Ree,A.H.,Bratland,A.,Nome,R.V.,Stokke,T.and Fodstad,O.(2003).Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1.Oncogene 22,8952-5.
Sasai,K.,Katayama,H.,Stenoien,D.L.,Fujii,S.,Honda,R.,Kimura,M.,Okano,Y,Tatsuka,M,Suzuki,F.,Nigg,E.A.et al.(2004).Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells.Cell Motil Cytoskeleton 59,249-63.
Sen,S.,Zhou,H.,Zhang,R.D.,Yoon,D.S.,Vakar-Lopez,F.,Ito,S.,Jiang,F.,Johnston,D.,Grossman,H.B.,Ruifrok,A.C.et al.(2002).Arnplification/overexpression of a mitotic kinase gene in human bladder cancer.J Natl Cancer Inst 94,1320-9.
Setoyama,T.,Natsugpe,S.,Okumura,H.,Matsumoto,M.,Uchikado,Y,Yokomakura,N.,Ishigami,S.and Aikou,T.(2007).alpha-catenin is a significant prognostic factor than E-cadherin in esophageal squamous cell carcinoma.J Surg Oncol 95,148-55.
Smith,M.R.,Wilson,M.L.,Hamanaka,R.,Chase,D.,Kung,H.,Longo,D.L.and Ferris,D.K.(1997).Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase.Biochem Biophys Res Commun 234,397-405.
Smits,V.A.,Klompmaker,R.,Arnaud,L.,Rijksen,G,Nigg,E.A.and Medema,R.H.(2000).Polo-like kinase-1 is a target of the DNA damage checkpoint.Nat Cell Biol 2,672-6.
Spankuch-Schmitt,B.,Bereiter-Hahn,J.,Kaufmann,M.and Strebhardt,K.(2002).Effect of RNA silencing of polo-like kinase-1 (PLK1)on apoptosis and spindle formation in human cancer cells.J Natl Cancer Inst 94,1863-77.
Spankuch,B.,Heim,S.,Kurunci-Csacsko,E.,Lindenau,C,Yuan,J.,Kaufmann,M.and Strebhardt,K.(2006).Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer Cells In vitro and In vivo.Cancer Res 66,5836-46.
Spankuch,B.,Matthess,Y.,Knecht,R.,Zimmer,B.,Kaufmann,M.and Strebhardt,K.(2004).Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1.J Natl Cancer Inst 96,862-72.
Steegmaier,M.,Hoffmann,M.,Baum,A.,Lenart,R,Petronczki,M.,Krssak,M.,Gurtler,U.,Garin-Chesa,P.,Lieb,S.,Quant,J.et al.(2007).BI 2536,a potent and selective inhibitor of polo-like kinase 1,inhibits tumor growth in vivo.Curr Biol 17,316-22.
Stenoien,D.L.,Sen,S.,Mancini,M.A.and Brinkley,B.R.(2003).Dynamic association of a tumor amplified kinase,Aurora-A,with the centrosome and mitotic spindle.Cell Motil Cytoskeleton 55,134-46.
Stevenson,C.S.,Capper,E.A.,Roshak,A.K.,Marquez,B.,Eichman,C,Jackson,J.R.,Mattern,M.,Gerwick,W.H.,Jacobs,R.S.and Marshall,L.A.(2002).The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore.J Pharmacol Exp Ther 303,858-66.
Strebhardt,K.and Ullrich,A.(2006).Targeting polo-like kinase 1 for cancer therapy.Nat Rev Cancer 6,321-30.
Sugiyama,K.,Sugiura,K.,Hara,T.,Sugimoto,K.,Shima,H.,Honda,K.,Furukawa,K.,Yamashita,S.and Urano,T.(2002).Aurora-B associated protein phosphatases as negative regulators of kinase activation.Oncogene 21,3103-11.
Sumara,I.,Vorlaufer,E.,Stukenberg,P.T.,Kelm,O.,Redemann,N.,Nigg,E.A.and Peters,J.M.(2002).The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase.Mol Cell 9,515-25.
Sunkel,C.E.and Glover,D.M.(1988).polo,a mitotic mutant of Drosophila displaying abnormal spindle poles.J Cell Sci 89 (Pt 1),25-38.
Swallow,C.J.,Ko,M.A.,Siddiqui,N.U.,Hudson,J.W.and Dennis,J.W.(2005).Sak/Plk4 and mitotic fidelity.Oncogene 24,306-12.
Takahashi,T.,Sano,B.,Nagata,T,Kato,H.,Sugiyama,Y,Kunieda,K.,Kimura,M.,Okano,Y and Saji,S.(2003).Polo-like kinase 1 (PLK1)is overexpressed in primary colorectal cancers.Cancer Sci 94,148-52.
Takai,N.,Hamanaka,R.,Yoshimatsu,J.and Miyakawa,I.(2005).Polo-like kinases (P1ks)and cancer.Oncogene 24,287-91.
Tirkkonen,M.,Tanner,M.,Karhu,R.,Kallioniemi,A.,Isola,J.and Kallioniemi,O.P.(1998).Molecular cytogenetics of primary breast cancer by CGH.Genes Chromosomes Cancer 21,177-84.
Tong,T.,Zhong,Y.,Kong,J.,Dong,L.,Song,Y,Fu,M.,Liu,Z.,Wang,M.,Guo,L.,Lu,S.et al.(2004).Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma.Clin Cancer Res 10,7304-10.
Toyoshima-Morimoto,F.,Taniguchi,E.and Nishida,E.(2002).Plkl promotes nuclear translocation of human Cdc25C during prophase.EMBO Rep 3,341-8.
Toyoshima-Morimoto,F.,Taniguchi,E.,Shinya,N.,Iwamatsu,A.and Nishida,E.(2001).Polo-like kinase 1 phosphorylates cyclin Bl and targets it to the nucleus during prophase.Nature 410,215-20.
Tsvetkov,L.,Xu,X.,Li,J.and Stern,D.F.(2003).Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody.J Biol Chem 278,8468-75.
Wall,N.R.,O'Connor,D.S.,Plescia,J.,Pommier,Y and Altieri,D.C.(2003).Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.Cancer Res 63,230-5.
Warnke,S.,Kemmler,S.,Hames,R.S.,Tsai,H.L.,Hoffmann-Rohrer,U.,Fry,A.M.and Hoffmann,I.(2004).Polo-like kinase-2 is required for centriole duplication in mammalian cells.Curr Biol 14,1200-7.
Wei,F.,Ni,J.,Wu,S.S.,Liu,H.,Xu,X.,Han,Y L.,Cai,Y,Zhang,J.W.,Chen,X.J.,Pang,H.et al.(2002).Cytogenetic studies of esophageal squamous cell carcinomas in the northern Chinese population by comparative genomic hybridization.Cancer Genet Cytogenet 138,38-43.
Weichert,W.,Denkert,C,Schmidt,M.,Gekeler,V.,Wolf,G,Kobel,M.,Dietel,M.and Hauptmann,S.(2004a).Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma.Br J Cancer 90,815-21.
Weichert,W.,Kristiansen,G,Schmidt,M.,Gekeler,V.,Noske,A.,Niesporek,S.,Dietel,M.and Denkert,C.(2005a).Polo-like kinase 1 expression is a prognostic factor in human colon cancer.World J Gastroenterol 11,5644-50.
Weichert,W.,Kristiansen,G,Winzer,K.J.,Schmidt,M.,Gekeler,V.,Noske,A.,Muller,B.M,Niesporek,S.,Dietel,M.and Denkert,C.(2005b).Polo-like kinase isoforms in breast cancer:expression patterns and prognostic implications.Virchows Arch 446,442-50.
Weichert,W.,Schmidt,M.,Gekeler,V.,Denkert,C,Stephan,C,Jung,K.,Loening,S.,Dietel,M.and Kristiansen,G.(2004b).Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades.Prostate 60,240-5.
Wolf,G,Elez,R.,Doermer,A.,Holtrich,U.,Ackermann,H.,Stutte,H.J.,Altmannsberger,H.M.,Rubsamen-Waigmartn,H.and Strebhardt,K.(1997).Prognostic significance of polo-like kinase (PLK)expression in non-small cell lung cancer.Oncogene 14,543-9.
Xie,S.,Wu,H.,Wang,Q.,Cogswell,J.P.,Husain,I.,Conn,C,Stambrook,P.,Jhanwar-Uniyal,M.and Dai,W.(2001).Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.J Biol Chem 276,43305-12.
Yamamoto,Y,Matsuyama,H.,Kawauchi,S.,Matsumoto,H.,Nagao,K.,Ohmi,C,Sakano,S.,Furuya,T.,Oga,A.,Naito,K.et al.(2006).Overexpression of Polo-Like Kinase 1 (PLK1)and Chromosomal Instability in Bladder Cancer.Oncology 70,231-237.
Yarm,F.R.(2002).Plk phosphorylation regulates the microtubule-stabilizing protein TCTP.Mol Cell Biol 22,6209-21.
Yu,X.,Minter-Dykhouse,K.,Malureanu,L.,Zhao,W.M.,Zhang,D.,Merkle,C.J.,Ward,I.M.,Saya,H.,Fang,G,van Deursen,J.et al.(2005).Chfr is required for tumor suppression and Aurora A regulation.Nat Genet 37,401-6.
Yuan,J.,Eckerdt,F.,Bereiter-Hahn,J.,Kurunci-Csacsko,E.,Kaufmann,M.and Strebhardt,K.(2002).Cooperative phosphorylation including the activity of
polo-like kinase 1 regulates the subcellular localization of cyclin B1.Oncogene 21,8282-92.
Zhou,H.,Kuang,J.,Zhong,L.,Kuo,W.L.,Gray,J.W.,Sahin,A.,Brinkley,B.R.and Sen,S.(1998).Tumour amplified kinase STK15/BTAK induces centrosome amplification,aneuploidy and transformation.Nat Genet 20,189-93.
Zhou,J.,O'Brate,A.,Zelnak,A.and Giarmakakou,P.(2004).Survivin deregulation in beta-tubulin mutant ovarian cancer cells-underlies their compromised mitotic response to taxol.Cancer Res 64,8708-14.
Zimmerman,W.C.and Erikson,R.L.(2007).Polo-like kinase 3 is required for entry into S phase.Proc Natl Acad Sci U S A 104,1847-52.
韩亚玲,魏芳,徐昕,蔡岩,陈宝生,王洁,夏书华,胡海,黄晓平,汉雨生et al.(2002).人食管鳞癌细胞系EC9706的建立及其比较基因组杂交分析.中华医学遗传学杂志19,455-7.