Ras信号通路对HeLa细胞增殖及FBW7、cyclin E表达的影响
摘要
目的:
研究Ras及其下游PI3K和MAPK信号通路对人类宫颈癌细胞株HeLa细胞增殖及细胞周期素E(cyclin E)表达的影响。在此基础上,进一步探讨介导cyclin E泛素化降解的抑癌蛋白F-盒和含蛋白7的WD重复结构域(FBW7)在HeLa细胞中的表达特点,并观察调控cyclin E表达的Ras下游信号通路对FBW7表达的影响。
方法:
1.以宫颈癌细胞株HeLa细胞为研究对象,观察Ras信号通路对HeLa细胞增殖、细胞周期分布及cyclin E表达的影响:不同浓度Ras信号通路阻断剂FTI-277处理HeLa细胞,噻唑兰比色(MTT)法检测FTI-277对HeLa细胞的增殖抑制率;流式细胞术(FCM)检测FTI-277对HeLa细胞细胞周期分布的影响;RT-PCR和Western blot检测FTI-277对HeLa细胞cyclin E的mRNA和蛋白水平表达的影响。
2.观察Ras下游PI3K和MAPK信号通路对HeLa细胞增殖及cyclin E表达的影响:不同浓度PI3K信号通路阻断剂LY-294002和MAPK信号通路阻断剂UO-126分别处理HeLa细胞,MTT法分别检测两者对HeLa细胞的增殖抑制率;RT-PCR和Western blot分别检测两者对HeLa细胞cyclin E的mRNA和蛋白水平表达的影响。
3.观察Ras下游调控cyclin E表达的MAPK信号通路对HeLa细胞FBW7表达的影响:RT-PCR和Western blot检测UO-126对HeLa细胞FBW7的mRNA和蛋白水平表达的影响;免疫荧光法观察HeLa细胞FBW7的分布及UO-126对HeLa细胞FBW7表达的影响。
结果:
1. MTT实验显示,Ras信号通路阻断剂FTI-277具有抑制HeLa细胞增殖的作用,且具有时效量效依赖性。结果显示10μmol/L的FTI-277药物浓度处理组线性相关性最好,因此,在后续的实验中我们采用10μmol/L的FTI-277作为干扰因素,探讨FTI-277对HeLa细胞周期及cyclin E表达的影响。FCM检测细胞周期结果显示,FTI-277作用后细胞周期滞留于G1/S期,且具有时间依赖性。RT-PCR和Western blot检测结果显示FTI-277作用后,HeLa细胞cyclin E mRNA水平无明显改变,cyclin E蛋白表达水平减弱。
2.PI3K信号通路阻断剂LY-294002和MAPK信号通路阻断剂UO-126均显示出抑制HeLa细胞增殖的作用,10μmol/L的LY-294002药物浓度处理组和10μmol/L的UO-126药物浓度处理组分别显示出最好的线性相关性,因此,实验中采用10μmol/L的LY-294002和10μmol/L的UO-126处理HeLa细胞,观察不同时间梯度下cyclin E表达的变化。LY-294002对cyclin E的蛋白表达无明显影响,相对之下,UO-126能下调cyclin E的蛋白表达。
3. RT-PCR和Western blot检测结果显示UO-126作用后,HeLa细胞FBW7 mRNA及蛋白表达均增多。免疫荧光结果显示,FBW7在HeLa细胞的细胞质和细胞核中有表达,细胞核部位表达较多。UO-126处理HeLa细胞后FBW7阳性表达增强,并具有时间依赖性。
结论:
1. HeLa细胞的异常增殖与Ras信号通路的激活有关,阻断Ras信号通路激活可以减慢HeLa细胞周期G1/S期的进程并下调cyclin E蛋白的表达。Ras-MAPK信号通路而不是Ras-PI3K信号通路在HeLa细胞cyclin E蛋白的表达调控中发挥重要作用。
2. HeLa细胞中泛素化降解cyclin E的抑癌蛋白FBW7表达也与Ras-MAPK信号通路有关。FBW7位于Ras-MAPK信号通路的下游。
Objective:
To study the effects of Ras and its downstream PI3K and MAPK signaling pathway on the proliferation and the expression of cyclin E in human cervical cancer HeLa cells.On this base,to further explore the expression characteristics of tumor suppressor protein F-box and WD repeat domain-containing protein7(FBW7) which mediated the ubiquitination degradation of cyclin E and to observe the effect of Ras downstream signaling pathway which regulated the expression of cyclin E on the expression of FBW7.
Methods:
1. Cervical cancer HeLa cells were used as the research model,the effects of Ras signaling pathway on the proliferation,cells cycle distribution and the expression of cyclin E were investigated in the following experiment.HeLa cells were treated with different concentrations of FTI-277 ,a Ras inhibitor,MTT assay was used to observe the proliferation of HeLa cells.Flow cytometry(FCM) was used to examine the growth cycles of the HeLa cells.The mRNA and protein expression of cyclin E were detected by RT-PCR and Western blot before and after Ras signal was blocked by FTI-277.
2. To observe the effects of PI3K signaling pathway and MAPK signaling pathway that lie downstream of Ras on the proliferation and the expression of cyclin E in HeLa cells. HeLa cells were treated with different concentrations of LY-294002 ,a PI3K inhibitor ,and UO-126,a MAPK inhibitor,HeLa cells proliferation inhibition rate was analysed by MTT test.Expression of cyclin E was detected by RT-PCR and Western blot.
3. To investigate the effect of Ras-MAPK signaling pathway regulating the expression of cyclin E on the expression of FBW7 in HeLa cells.The MAPK signaling pathway was blocked by UO-126,the mRNA and protein expression of FBW7 were detected by RT-PCR and Western blot.Immunofluorescence showed the location and expression of FBW7 in HeLa cells.
Results:
1. MTT test showed HeLa cells proliferation was inhibited by FTI-277,a Ras signaling pathway inhibitor,in time-dependent and dose-dependent way.The results indicated that FTI-277 were in 10μmol/L treatment groups which had the best linear relationship.Therefore,we have chosen 10μmol / L as the interfering factors to observe FTI-277 on cells cycle and cyclin E expression at different time. Flow cytometry showed that FTI-277 blocked Hela cells in G1/S phase in a time dependent way. Cyclin E mRNA expression in HeLa cells treated with FTI-277 had no significant change, but the level of cyclin E protein expression was significantly reduced.
2. MTT test demonstrated that both PI3K pathway inhibitor LY-294002 and MAPK pathway inhibitor UO-126 inhibited the proliferation of HeLa cells,10μmol/L LY-294002 treatment group and 10μmol/L UO-126 treatment group had the approximat best linear correlation.Then cyclin E protein expressions were observed at various intervals of 10μmol / L LY-294002 and 10μmol/L UO-126 treatment.The protein level of cyclin E was not affected by LY-294002.In contrast,UO-126 reduced the level of cyclin E protein expression.
3. RT-PCR and Western blot exhibited that the FBW7 mRNA and protein expression had significantly increased after HeLa cells were treated with UO-126. Immunofluorescence showed that the positive FBW7 was mainly found in cytoplasm and nucleus of HeLa cells and nuclear FBW7 expression was more.The expression of positive FBW7 had increased after HeLa cells were treated with UO-126 in a time dependent way.
Conclusion:
1. The abnormal proliferation of HeLa cells were associated with the activation of Ras signaling pathway. Blocking Ras signaling pathway could slow down HeLa cells cycle G1/S phase transition and decrease the expression of cyclin E. Ras-MAPK signaling pathway not Ras-PI3K signaling pathway should be essential for regulation of cyclin E expression in HeLa cells.
2. The expression of tumor suppressor protein FBW7 which mediated the ubiquitination degradation of cyclinE could have some relevance to the Ras-MAPK signaling pathway. FBW7 lied downstream of Ras-MAPK signaling pathway.
研究Ras及其下游PI3K和MAPK信号通路对人类宫颈癌细胞株HeLa细胞增殖及细胞周期素E(cyclin E)表达的影响。在此基础上,进一步探讨介导cyclin E泛素化降解的抑癌蛋白F-盒和含蛋白7的WD重复结构域(FBW7)在HeLa细胞中的表达特点,并观察调控cyclin E表达的Ras下游信号通路对FBW7表达的影响。
方法:
1.以宫颈癌细胞株HeLa细胞为研究对象,观察Ras信号通路对HeLa细胞增殖、细胞周期分布及cyclin E表达的影响:不同浓度Ras信号通路阻断剂FTI-277处理HeLa细胞,噻唑兰比色(MTT)法检测FTI-277对HeLa细胞的增殖抑制率;流式细胞术(FCM)检测FTI-277对HeLa细胞细胞周期分布的影响;RT-PCR和Western blot检测FTI-277对HeLa细胞cyclin E的mRNA和蛋白水平表达的影响。
2.观察Ras下游PI3K和MAPK信号通路对HeLa细胞增殖及cyclin E表达的影响:不同浓度PI3K信号通路阻断剂LY-294002和MAPK信号通路阻断剂UO-126分别处理HeLa细胞,MTT法分别检测两者对HeLa细胞的增殖抑制率;RT-PCR和Western blot分别检测两者对HeLa细胞cyclin E的mRNA和蛋白水平表达的影响。
3.观察Ras下游调控cyclin E表达的MAPK信号通路对HeLa细胞FBW7表达的影响:RT-PCR和Western blot检测UO-126对HeLa细胞FBW7的mRNA和蛋白水平表达的影响;免疫荧光法观察HeLa细胞FBW7的分布及UO-126对HeLa细胞FBW7表达的影响。
结果:
1. MTT实验显示,Ras信号通路阻断剂FTI-277具有抑制HeLa细胞增殖的作用,且具有时效量效依赖性。结果显示10μmol/L的FTI-277药物浓度处理组线性相关性最好,因此,在后续的实验中我们采用10μmol/L的FTI-277作为干扰因素,探讨FTI-277对HeLa细胞周期及cyclin E表达的影响。FCM检测细胞周期结果显示,FTI-277作用后细胞周期滞留于G1/S期,且具有时间依赖性。RT-PCR和Western blot检测结果显示FTI-277作用后,HeLa细胞cyclin E mRNA水平无明显改变,cyclin E蛋白表达水平减弱。
2.PI3K信号通路阻断剂LY-294002和MAPK信号通路阻断剂UO-126均显示出抑制HeLa细胞增殖的作用,10μmol/L的LY-294002药物浓度处理组和10μmol/L的UO-126药物浓度处理组分别显示出最好的线性相关性,因此,实验中采用10μmol/L的LY-294002和10μmol/L的UO-126处理HeLa细胞,观察不同时间梯度下cyclin E表达的变化。LY-294002对cyclin E的蛋白表达无明显影响,相对之下,UO-126能下调cyclin E的蛋白表达。
3. RT-PCR和Western blot检测结果显示UO-126作用后,HeLa细胞FBW7 mRNA及蛋白表达均增多。免疫荧光结果显示,FBW7在HeLa细胞的细胞质和细胞核中有表达,细胞核部位表达较多。UO-126处理HeLa细胞后FBW7阳性表达增强,并具有时间依赖性。
结论:
1. HeLa细胞的异常增殖与Ras信号通路的激活有关,阻断Ras信号通路激活可以减慢HeLa细胞周期G1/S期的进程并下调cyclin E蛋白的表达。Ras-MAPK信号通路而不是Ras-PI3K信号通路在HeLa细胞cyclin E蛋白的表达调控中发挥重要作用。
2. HeLa细胞中泛素化降解cyclin E的抑癌蛋白FBW7表达也与Ras-MAPK信号通路有关。FBW7位于Ras-MAPK信号通路的下游。
Objective:
To study the effects of Ras and its downstream PI3K and MAPK signaling pathway on the proliferation and the expression of cyclin E in human cervical cancer HeLa cells.On this base,to further explore the expression characteristics of tumor suppressor protein F-box and WD repeat domain-containing protein7(FBW7) which mediated the ubiquitination degradation of cyclin E and to observe the effect of Ras downstream signaling pathway which regulated the expression of cyclin E on the expression of FBW7.
Methods:
1. Cervical cancer HeLa cells were used as the research model,the effects of Ras signaling pathway on the proliferation,cells cycle distribution and the expression of cyclin E were investigated in the following experiment.HeLa cells were treated with different concentrations of FTI-277 ,a Ras inhibitor,MTT assay was used to observe the proliferation of HeLa cells.Flow cytometry(FCM) was used to examine the growth cycles of the HeLa cells.The mRNA and protein expression of cyclin E were detected by RT-PCR and Western blot before and after Ras signal was blocked by FTI-277.
2. To observe the effects of PI3K signaling pathway and MAPK signaling pathway that lie downstream of Ras on the proliferation and the expression of cyclin E in HeLa cells. HeLa cells were treated with different concentrations of LY-294002 ,a PI3K inhibitor ,and UO-126,a MAPK inhibitor,HeLa cells proliferation inhibition rate was analysed by MTT test.Expression of cyclin E was detected by RT-PCR and Western blot.
3. To investigate the effect of Ras-MAPK signaling pathway regulating the expression of cyclin E on the expression of FBW7 in HeLa cells.The MAPK signaling pathway was blocked by UO-126,the mRNA and protein expression of FBW7 were detected by RT-PCR and Western blot.Immunofluorescence showed the location and expression of FBW7 in HeLa cells.
Results:
1. MTT test showed HeLa cells proliferation was inhibited by FTI-277,a Ras signaling pathway inhibitor,in time-dependent and dose-dependent way.The results indicated that FTI-277 were in 10μmol/L treatment groups which had the best linear relationship.Therefore,we have chosen 10μmol / L as the interfering factors to observe FTI-277 on cells cycle and cyclin E expression at different time. Flow cytometry showed that FTI-277 blocked Hela cells in G1/S phase in a time dependent way. Cyclin E mRNA expression in HeLa cells treated with FTI-277 had no significant change, but the level of cyclin E protein expression was significantly reduced.
2. MTT test demonstrated that both PI3K pathway inhibitor LY-294002 and MAPK pathway inhibitor UO-126 inhibited the proliferation of HeLa cells,10μmol/L LY-294002 treatment group and 10μmol/L UO-126 treatment group had the approximat best linear correlation.Then cyclin E protein expressions were observed at various intervals of 10μmol / L LY-294002 and 10μmol/L UO-126 treatment.The protein level of cyclin E was not affected by LY-294002.In contrast,UO-126 reduced the level of cyclin E protein expression.
3. RT-PCR and Western blot exhibited that the FBW7 mRNA and protein expression had significantly increased after HeLa cells were treated with UO-126. Immunofluorescence showed that the positive FBW7 was mainly found in cytoplasm and nucleus of HeLa cells and nuclear FBW7 expression was more.The expression of positive FBW7 had increased after HeLa cells were treated with UO-126 in a time dependent way.
Conclusion:
1. The abnormal proliferation of HeLa cells were associated with the activation of Ras signaling pathway. Blocking Ras signaling pathway could slow down HeLa cells cycle G1/S phase transition and decrease the expression of cyclin E. Ras-MAPK signaling pathway not Ras-PI3K signaling pathway should be essential for regulation of cyclin E expression in HeLa cells.
2. The expression of tumor suppressor protein FBW7 which mediated the ubiquitination degradation of cyclinE could have some relevance to the Ras-MAPK signaling pathway. FBW7 lied downstream of Ras-MAPK signaling pathway.
引文
[1] Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer[J]. Cancer Res ,2002,62:4535-4539.
[2] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer[J].Nat Rev Cancer ,2008, 8: 438-449.
[3] Welcker M, Clurman BE. ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008, 8:83-93.
[4] Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer[J]. Cancer Res ,2002,62:4535-4539.
[5] Willmarth NE,Albertson DG,Ethier SP.Chromosomalinstability and lack of cyclin E regulation in hCdc4 mutanthuman breast cancer cells[J].Breast Cancer Res,2004,6:R531-539.
[6] Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene(CCNE) amplification and hCDC4 mutations in endometrial carcinoma[J].Pathol, 2003,201:589-595.
[7] Kwak EL, Moberg KH, Wahrer DC, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer[J].Gynecol Oncol, 2005,98:124-128.
[8] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7,AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003,163:1255-1260.
[9] Song JH, Schnittke N, Zaat A, et al. FBXW7 mutation in adult T-cell and B-cell acute lymphocytic leukemias[J]. Leuk Res,2008, 32:1751-1755.
[10] Stubbert LJ, Spronck JC, Hamill JD, et al.Ultraviolet light induces the sustained unscheduled expression of cyclin E in the absence of functional p53[J]. Cell Cycle, 2009, 8(18):2995-3002.
[11] Spruck CH, Won KA, Reed SI.Deregulated cyclin E induces chromosome instability[J].Nature, 1999,401(6750):297–300.
[12] Ekholm-Reed S, Méndez J, Tedesco D, et al.Deregulation of cyclin E in human cells interferes with prereplication complex assembly[J]. Cell Biol,2004,165(6):789-800.
[13] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[14] Durcan TM, Halpin ES, Casaletti L, et al.Centrosome duplication proceeds during mimosine-induced G1 cell cycle arrest[J]. Cell Physiol,2008,215(1):182-191.
[15] Hinchcliffe EH, Li C, Thompson EA, et al.Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts[J]. Science,1999, 283 (5403):851-854.
[16] Chen Z, Indjeian VB, McManus M, et al.CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells[J]. Dev Cell ,2002,3(3):339-350.
[17] Okuda M, Horn HF, Tarapore P, et al.Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication[J]. Cell, 2000,103(1):127-140.
[18] Yan G, Young-ML, Markus W, et al.Kinase-Independent Function of Cyclin E [J]. Molecular Cell,2007,25(12):127-139.
[19] Kim YT, Zhao M. Aberrant cell cycle regulation in cervical carcinoma[J]. Yonsei Med , 2005, 46(5):597-613.
[20] Van de Putte G, Kristensen GB, Lie AK, et al.Cyclins and proliferation markers in early squamous cervical carcinoma[J].Gynecol Oncol,2004, 92(1):40-46.
[21] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Cancer,2003, 104(3):369-375.
[22] Koepp DM, Schaefer LK, Ye X, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science, 2001, 294:173-177.
[23] Ekholm-Reed S, Spruck CH, Sangfelt O, et al. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer[J]. Cancer Res, 2004,64:795-800.
[24] Sangfelt O, Cepeda D, Malyukova A, et al. Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do notoverexpress cyclin E[J].Cell Cycle,2008,7:1075-1082.
[25] Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7)[J].Cell Cycle,2005, 4:1356-1359.
[26] Moberg KH, Bell DW, Wahrer DC, et al. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines[J]. Nature,2001,413: 311-316.
[27] Susanna ER, Spruck CH, Spruck R, et al. Mutation of hCDC4 Leads to Cell Cycle Deregulation of Cyclin E in cancer[J].Cancer Rescarch,2004,64: 795-800.
[28] Sagae S, Kudo R, Kuzumaki N, et al.Ras oncogene expression and progression in intraepithelial neoplasia of the uterine cervix[J].Cancer,1990,66(2):295-301.
[29] Lee HP, Kim WJ, Kim JH , et al. Expression of ras oncogene in cervical carcinoma and its relevance to prognosis[J]. Gynecol Oncol Colposc,1993,4(1):32-42.
[30] Adili A, Aphrothiti J. Fikaris, OM, et al. Ras induces chromosome instability and abrogation of the DNA damage response[J].Cancer Res,2006,66(21):10505-10512.
[31] Mammas IN, Zafiropoulos A, Koumantakis E ,et al.Transcriptional activation of H- and N-ras oncogenes in human cervical cancer[J]. Gynecol Oncol. 2004,92(3): 941-948.
[32] Mora N, Rosales R, Rosales C.R-Ras promotes metastasis of cervical cancer epithelial cells[J]. Cancer Immunol Immunother. 2007,56(4):535-544.
[33] Enomoto T, Inoue M, Perantoni AO,et al. K-ras activation in premalignant and malignant epithelial lesions of the human uterus[J]. Cancer Res. 1991,51(19): 5308-5314.
[34] Nair SA, Nair MB, Jayaprakash PG, et al. ras and c-myc oncoproteins during tumor progression in the uterine cervix[J].Tumori. 1998 ,84(5):583-588.
[35] Campbell SL, Khosravi-Far R, Rossman KL, et al. Increasing complexity of Ras signaling[J]. Oncogene ,1998,17:1395-1413.
[36] Engelbrecht AM, Gebhardt S, Louw L. Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis[J].cancer letter,2006, 235(1):93-99.
[37] Sun H, Zhu Q, Ren J, et al. Influce of lysophosphatidic acid on proliferation, adhesion,migration and apoptosis of cervical cancer HeLa cells[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2009,25(8):702-705.
[38] Takuwa N, Takuwa Y. Regulation of cell cycle molecules by the Ras effector system[J]. Mol Cell Endocrinol,2001 ,177(1-2):25-33.
[39] Aktas H, Cai H, Cooper GM. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1[J]. Mol Cell Biol,1997,17(7):3850-3857.
[40]宋鑫,曹亚.G 1/S检测点调控与癌变多阶段关系[J].国外医学·分子生物学分册,2002,24(2):73-76.
[41] Donnellan R,Chetty AR. Cyclin E in human cancers [J].FASEB,1999,13: 773-780.
[42]李长民,庄如锦,李佩玲,等. p27和cyclin E在宫颈癌中的表达及其临床意义[J].中国现代医学杂志,2005,15(11)1651-1654.
[43]韦毓,庞朗,冯秀英. PTEN、CyclinE与子宫内膜癌[J].柳州医学,2006,19(2):101-104.
[44] Rosen DG, Yang G, Deavers MT ,et al . Cyclin E Expression Is Correlated with Tumor Progression and Predicts a Poor Prognosis in Patients with Ovarian Carcinoma [J].Cancer, 2006,106 (9 )1925-1932.
[45]周奇,粱力建,彭宝岗,等.肝细胞癌中p27、cyclin E和cyclin A的表达及相关分析[J].中山大学学报(医学科学版) ,2006 ,27 (3S ):60-63.
[46]胃癌石玉宝,刘晓杰,李勇,等. CyelinE在胃癌中的表达及其与临床生物学行为关系的研究[J].现代肿瘤医学,2008,16(12 ):2113-2115.
[47]杨彦,王力,程若川.大肠癌中Cyc I i n E、p27的表达及意义[J].中华临床医药,2003 ,4 (23 ):32-35.
[48] Hui Y, ping YJ, Xin Z, et al. Expression of p57 k p2 and cyclinE proteins in human pancreatic cancer[J]. Chinese Medical ,2003,116(6):944-946.
[49] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Int J Cancer,2003, 104(3):369-375.
[50] Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles[J]. Oncogene,2005, 24:2776-2786.
[51] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[52]谢宛玉,马艳.宫颈癌P27蛋白、CyclinE蛋白表达的研究[J].美国中华临床医学杂志,2002 ,4 (1) 34-36.
[53] Pruitt K, Pestell RG, Der CJ. Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells[J ].Biol Chem,2000 ,275(52):40916-40924.
[54] Hitomi M , Stacey DW. Ras-dependent cell cycle commitment during G2 phase[J].FESB Lett,2001,490:123-131.
[55] Pruitt K, Pestell RG, Der CJ. Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells[J ].Biol Chem,2000 ,275(52):40916-40924.
[56] Hitomi M , Stacey DW . Ras-dependent cell cycle commitment during G2 phase[J].FESB Lett,2001,490:123-131.
[57] Jeong SN, Yoshinori I, Michiie S, et al.Ras Farnesylation Inhibitor FTI-277 Restores the E-Cadherin/Catenin Cell[J].Cancer Res,2002, 93(9):1020-1028.
[58] Prober DA, Edgar BA.Ras1 promotes cellular growth in the Drosophila wing[J]. Cell,2000, 100(4):435-446.
[59] Wingate H, Puskas A, Duong M, et al.Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression[J]. Cell Cycle, 2009,8(7):1062-1068.
[60] Mull BB, Cox J, Bui T, et al.Post-translational modification and stability of low molecular weight cyclin E[J].Oncogene,2009, 28(35):3167-3176.
[61] Kasahara K, Nakayama Y, Nakazato Y , et al.Src signaling regulates completion of abscission in cytokinesis through ERK/MAPK activation at the midbody[J]. Biol Chem,2007,282(8):5327-5339.
[62] ChristopherM. L,Christa BF,Vicente P, et al.Phosphatidylinositol 3-Kinase Inhibition by LY294002 Radiosensitizes Human Cervical Cancer Cell Lines[J].Cancer Res 2006,12(1):250-256.
[63] Wier?d L, Rosseland CM, Lindeman B, et al.CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes[J]. Cell Prolif, 2007,40(4):475-487.
[64] Gao N, Flynn DC, Zhang Z, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells[J]. Cell Physiol,2004,287(2):C281-C291.
[65] Hartwell LH, Mortimer RK, Culotti J, et al. Genetic control of the cell division cycle in yeast: V.genetic analysis of cdc mutants[J]. Genetics, 1973,74:267-286.
[66] Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans[J].Genetics, 1993,135:765-783 .
[67] Hubbard EJ, Wu G, Kitajewski J, et al. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins[J]. Genes Dev, 1997,11:3182-3193.
[68] Oberg C, Li JH, Pauley A, et al. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog[J]. Biol. Chem,2001,2 76:35847-35853 .
[69] Wu, G, Svetlana L, Indranil D,et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation[J].Cell. Biol,2001,21: 7403-7415 .
[70] Gupta-Rossi N, Le Bail O, Gonen H, Brou C, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor[J]. Biol. Chem, 2001,276:34371-34378 .
[71] Nakayama KI, Nakayama K. Ubiquitin ligases:cell-cycle control and cancer[J]. Nature Rev Cancer, 2006, 6:369-381.
[72] Yada M, Hatakeyama S, Kamura T, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7[J].EMBO,2004, 23(10):2116- 2125.
[73] Bonetti P, Davoli T, Sironi C, et al.Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma[J].Cell Biol,2008, 182:19-26.
[74] Nateri AS, Riera-Sans L, Da Costa C, et al. The ubiquitin ligase SCF Fbw7 antagonizes apoptotic JNK signaling [J]. Sci, 2004, 303(5662): 1374-1378.
[75] Anzi S, Finkin S, Shaulian E. Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV[J].Cell Signal,2008, 20:862-871.
[76] Wu G, Lyapina I, Das J, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation[J]. Cell Biol,2001, 21:7403-7415.
[77] O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors[J]. Exp Med,2007, 204:1813-1824.
[78] Kitagawa K, Hiramatsu Y, Uchida C, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb[J]. Oncogene,2009, 28:2393-2405.
[79] Welcker M, Clurman BE. Fbw7/hCDC4 dimerization regulates its substrate interactions[J]. Cell Div,2007,2,7.
[80] Mao JH, Perez-Losada J, Wu D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene[J]. Nature,2004,432:775-779.
[81] Welcker M, Orian A, Grim JA, et al. A Nucleolar Isoform of the Fbw7 Ubiquitin Ligase Regulates c-Myc and Cell Size[J].Cur Biol, 2004,14:1852-1857.
[82] Wei Z, Deanna MK. Fbw7 Isoform Interation Contributes to Cyclin E Proteolysis[J].Cancer Res,2006,4:935-943.
[83] Grim JE, Gustafson MP,Hirata RK, et al. Isoform-and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J].Cell Biol,2008,181:913-920.
[1] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer[J].Nat Rev Cancer ,2008, 8: 438-449.
[2] Nakayama KI, Nakayama K. Ubiquitin ligases:cell-cycle control and cancer[J]. Nature Rev Cancer, 2006, 6:369-381.
[3] Welcker M, Clurman BE. ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008, 8:83-93.
[4] Hartwell LH, Mortimer RK, Culotti J, et al. Genetic control of the cell division cycle in yeast: V.genetic analysis of cdc mutants[J]. Genetics, 1973,74:267-286.
[5] Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans[J].Genetics, 1993,135:765-783.
[6] Hubbard EJ, Wu G, Kitajewski J, et al. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins[J]. Genes Dev, 1997,11:3182-3193.
[7] Oberg C, Li JH, Pauley A, et al. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog[J].Biol. Chem,2001,276:35847-35853.
[8] Wu, G, Svetlana L, Indranil D,et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation[J].Cell. Biol,2001,21: 7403-7415.
[9] Gupta-Rossi N, Le Bail O, Gonen H, Brou C, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor[J]. Biol. Chem, 2001,276:34371-34378.
[10] Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer[J]. Cancer Res ,2002,62:4535-4539.
[11] Bai C, Sen P, Hofmann K, et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box[J]. Cell, 1996,86:263-274.
[12] Hao B, Oehlmann S, Sowa ME, et al. Structure of a Fbw7–Skp1–cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases[J]. Mol. Cell ,2007,26:131-143.
[13] Welcker M, Clurman BE. Fbw7/hCDC4 dimerization regulates its substrate interactions[J]. Cell Div,2007,2,7.
[14] Tang X, Orlicky S, Lin Z, et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination[J]. Cell, 2007,129:1165-1176.
[15] Zhang W, Koepp DM. Fbw7 isoform interaction contributes to cyclin E proteolysis[J]. Cancer Res,2006, 4:935-943.
[16] Kimura T, Gotoh M, Nakamura Y, et al. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53[J].Cancer Sci,2003,94:431-436.
[17] Welcker M, Orian A, Grim JE, et al. A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size[J]. Curr Biol, 2004,14:1852-1857.
[18] Ye, X, Nalepa G, Welcker M, et al. Recognition of phosphodegron motifs in human cyclin E by the SCFFbw7 ubiquitin ligase[J].Biol. Chem,2004,279: 50110-50119.
[19] Nash P, Tang X, Orlicky S, et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication[J]. Nature ,2001,414:514-521.
[20] Koepp DM, Schaefer LK, Ye X, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science, 2001, 294:173-177.
[21] Ekholm-Reed S, Spruck CH, Sangfelt O, et al. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer[J]. Cancer Res, 2004,64:795-800.
[22] Sangfelt O, Cepeda D, Malyukova A, et al. Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do not overexpress cyclin E[J].Cell Cycle,2008,7:1075-1082.
[23] Grim JE, Gustafson MP, Hirata RK, et al. Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J]. Cell Biol, 2008,181:913-920.
[24] Yada M, Hatakeyama S, Kamura T, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7[J].EMBO,2004, 23(10):2116-2125.
[25] Bonetti P, Davoli T, Sironi C, et al.Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma[J].Cell Biol,2008, 182:19-26.
[26] Nateri AS, Riera-Sans L, Da Costa C, et al. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling[J].Sci,2004,303(5662):1374-1378.
[27] Anzi S, Finkin S, Shaulian E. Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV[J].Cell Signal,2008, 20:862-871.
[28] Wu G, Lyapina I, Das J, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation[J]. Cell.Biol, 2001,21: 7403-7415.
[29] O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors[J]. Exp Med,2007, 204:1813-1824.
[30] Kitagawa K, Hiramatsu Y, Uchida C, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb[J]. Oncogene,2009, 28:2393-2405.
[31] Willmarth NE,Albertson DG,Ethier SP.Chromosomalinstability and lack of cyclin E regulation in hCdc4 mutanthuman breast cancer cells[J].Breast Cancer Res,2004,6:R531-539.
[32] Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene(CCNE) amplification and hCDC4 mutations in endometrial carcinoma[J].Pathol, 2003,201:589-595.
[33] Kwak EL, Moberg KH, Wahrer DC, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer[J].Gynecol Oncol, 2005,98:124-128.
[34] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7,AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003,163:1255-1260.
[35] Song JH, Schnittke N, Zaat A, et al. FBXW7 mutation in adult T-cell and B-cellacute lymphocytic leukemias[J]. Leuk Res,2008, 32:1751-1755.
[36] Thompson BJ, Jankovic V, Gao J, et al. Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7[J]. Exp Med,2008, 205:1395-1408.
[37] Mao JH, Perez-Losada J, Wu D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene[J]. Nature,2004,432:775-779.
[38] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Int J Cancer,2003, 104(3):369-375.
[39] Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles[J]. Oncogene,2005, 24:2776-2786.
[40] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[41] Spruck CH, Won KA, Reed SI.Deregulated cyclin E induces chromosome instability[J]. Nature, 1999,401(6750):297-300.
[42] Clurman BE, Sheaff RJ, Thress K, et al. Turnover of cyclin E by the ubiquitinproteasome pathway is regulated by cdk2 binding and cyclin phosphorylation[J]. Genes Dev,1996,10:1979-1990.
[43] Won KA, Reed SI. Activation of cyclinE/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E[J]. EMBO,1996, 15: 4182-4193.
[44] Strohmaier H, Spruck CH, Kaiser P, et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line[J].Nature, 2001,413:316-322.
[45] Moberg KH, Mukherjee A, Veraksa A, et al. The Drosophila F Box Protein Archipelago Regulates dMyc Protein Levels In Vivo[J].Curr. Biol,2004,14: 965-974.
[46] Koepp DM, Schaefer LK, Ye X,et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science,2001,294:173-177.
[47] Welcker M, Singer J, Loeb KR, et al. Multisite phosphorylation by Cdk2 and GSK3controls cyclin E degradation[J].Cell,2003,12:381-392.
[48] Welcker M,Clurman BE.FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008,8(2):83-93.
[49] Moberg KH, Bell DW, Wahrer DC, et al. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines[J]. Nature,2001,413: 311-316.
[50] Susanna ER, Spruck CH, Spruck R, et al. Mutation of hCDC4 Leads to Cell Cycle Deregulation of Cyclin E in cancer[J].Cancer Rescarch,2004,64: 795-800.
[51] Grandori C, Cowley SM, James LP, et al. The Myc/Max/Mad network and the transcriptional control of cell behavior[J]. Cell ,2000,16:653-699.
[52] Amati B. Myc degradation: dancing with ubiquitin ligases[J]. Sci, 2004,101:8843-8844.
[53] Angel P, Karin M. The role of jun,fos and the AP-1 complex in cell proliferation and transformation[J].Biochem Biophys Acta,1991,1072:129-159.
[54] Wei W, Jin J, Schlisio S, et al. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase[J]. Cancer Cell, 2005,8(1):25-33.
[55] Welcker M, Clurman BE.The SV40 Large T Antigen Contains a Decoy Phosphodegron That Mediates Its Interactions with Fbw7/hCdc4*[J]Biol Chem,2005,280(9):7654-7658.
[56] Lai, EC.. Protein degradation: four E3s for the Notch pathway[J]. Curr.Biol, 2002,12(2):74-78.
[57] Tetzlaff MT, Yu W, Li M, et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein[J]. Sci,2004,101: 3338-3345.
[58] Tsunematsu R, Nakayama K, Oike Y, et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development[J].Bio Chemistry, 2004, 279(10):9417-9423.
[59] Jung-Soon M, Mi-Yeon K, Seung-Ok H, et al. Integrin-Linked Kinase ControlsNotch1 Signaling by Down-Regulation of Protein Stability through Fbw7 Ubiquitin Ligase[J]. Cell. Biol, 2007,27: 5565-5574.
[60] Jennifer ON, Jonathan G, Peter S, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to -secretase inhibitors[J]. Exp. Med,2007, 204: 1813-1824.
[61] Rajagopalan H, Jallepalli PV, Rago C, et al. Inactivation of hCDC4 can cause chromosomal instability[J]. Nature,2004, 428(6978):77-81.
[62] Welcker M, Orian A, Grim JA, et al. A Nucleolar Isoform of the Fbw7 Ubiquitin Ligase Regulates c-Myc and Cell Size[J]. Cur Biol, 2004,14:1852-1857.
[63] Wei Z, Deanna MK. Fbw7 Isoform Interation Contributes to Cyclin E Proteolysis[J].Cancer Res,2006,4:935-943.
[64] Grim JE, Gustafson MP,Hirata RK, et al. Isoform-and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J].Cell Biol,2008,181:913-920.
[65] Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7)[J].Cell Cycle,2005, 4:1356-1359.
[66] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003, 163:1255-1260.
[2] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer[J].Nat Rev Cancer ,2008, 8: 438-449.
[3] Welcker M, Clurman BE. ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008, 8:83-93.
[4] Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer[J]. Cancer Res ,2002,62:4535-4539.
[5] Willmarth NE,Albertson DG,Ethier SP.Chromosomalinstability and lack of cyclin E regulation in hCdc4 mutanthuman breast cancer cells[J].Breast Cancer Res,2004,6:R531-539.
[6] Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene(CCNE) amplification and hCDC4 mutations in endometrial carcinoma[J].Pathol, 2003,201:589-595.
[7] Kwak EL, Moberg KH, Wahrer DC, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer[J].Gynecol Oncol, 2005,98:124-128.
[8] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7,AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003,163:1255-1260.
[9] Song JH, Schnittke N, Zaat A, et al. FBXW7 mutation in adult T-cell and B-cell acute lymphocytic leukemias[J]. Leuk Res,2008, 32:1751-1755.
[10] Stubbert LJ, Spronck JC, Hamill JD, et al.Ultraviolet light induces the sustained unscheduled expression of cyclin E in the absence of functional p53[J]. Cell Cycle, 2009, 8(18):2995-3002.
[11] Spruck CH, Won KA, Reed SI.Deregulated cyclin E induces chromosome instability[J].Nature, 1999,401(6750):297–300.
[12] Ekholm-Reed S, Méndez J, Tedesco D, et al.Deregulation of cyclin E in human cells interferes with prereplication complex assembly[J]. Cell Biol,2004,165(6):789-800.
[13] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[14] Durcan TM, Halpin ES, Casaletti L, et al.Centrosome duplication proceeds during mimosine-induced G1 cell cycle arrest[J]. Cell Physiol,2008,215(1):182-191.
[15] Hinchcliffe EH, Li C, Thompson EA, et al.Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts[J]. Science,1999, 283 (5403):851-854.
[16] Chen Z, Indjeian VB, McManus M, et al.CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells[J]. Dev Cell ,2002,3(3):339-350.
[17] Okuda M, Horn HF, Tarapore P, et al.Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication[J]. Cell, 2000,103(1):127-140.
[18] Yan G, Young-ML, Markus W, et al.Kinase-Independent Function of Cyclin E [J]. Molecular Cell,2007,25(12):127-139.
[19] Kim YT, Zhao M. Aberrant cell cycle regulation in cervical carcinoma[J]. Yonsei Med , 2005, 46(5):597-613.
[20] Van de Putte G, Kristensen GB, Lie AK, et al.Cyclins and proliferation markers in early squamous cervical carcinoma[J].Gynecol Oncol,2004, 92(1):40-46.
[21] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Cancer,2003, 104(3):369-375.
[22] Koepp DM, Schaefer LK, Ye X, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science, 2001, 294:173-177.
[23] Ekholm-Reed S, Spruck CH, Sangfelt O, et al. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer[J]. Cancer Res, 2004,64:795-800.
[24] Sangfelt O, Cepeda D, Malyukova A, et al. Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do notoverexpress cyclin E[J].Cell Cycle,2008,7:1075-1082.
[25] Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7)[J].Cell Cycle,2005, 4:1356-1359.
[26] Moberg KH, Bell DW, Wahrer DC, et al. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines[J]. Nature,2001,413: 311-316.
[27] Susanna ER, Spruck CH, Spruck R, et al. Mutation of hCDC4 Leads to Cell Cycle Deregulation of Cyclin E in cancer[J].Cancer Rescarch,2004,64: 795-800.
[28] Sagae S, Kudo R, Kuzumaki N, et al.Ras oncogene expression and progression in intraepithelial neoplasia of the uterine cervix[J].Cancer,1990,66(2):295-301.
[29] Lee HP, Kim WJ, Kim JH , et al. Expression of ras oncogene in cervical carcinoma and its relevance to prognosis[J]. Gynecol Oncol Colposc,1993,4(1):32-42.
[30] Adili A, Aphrothiti J. Fikaris, OM, et al. Ras induces chromosome instability and abrogation of the DNA damage response[J].Cancer Res,2006,66(21):10505-10512.
[31] Mammas IN, Zafiropoulos A, Koumantakis E ,et al.Transcriptional activation of H- and N-ras oncogenes in human cervical cancer[J]. Gynecol Oncol. 2004,92(3): 941-948.
[32] Mora N, Rosales R, Rosales C.R-Ras promotes metastasis of cervical cancer epithelial cells[J]. Cancer Immunol Immunother. 2007,56(4):535-544.
[33] Enomoto T, Inoue M, Perantoni AO,et al. K-ras activation in premalignant and malignant epithelial lesions of the human uterus[J]. Cancer Res. 1991,51(19): 5308-5314.
[34] Nair SA, Nair MB, Jayaprakash PG, et al. ras and c-myc oncoproteins during tumor progression in the uterine cervix[J].Tumori. 1998 ,84(5):583-588.
[35] Campbell SL, Khosravi-Far R, Rossman KL, et al. Increasing complexity of Ras signaling[J]. Oncogene ,1998,17:1395-1413.
[36] Engelbrecht AM, Gebhardt S, Louw L. Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis[J].cancer letter,2006, 235(1):93-99.
[37] Sun H, Zhu Q, Ren J, et al. Influce of lysophosphatidic acid on proliferation, adhesion,migration and apoptosis of cervical cancer HeLa cells[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2009,25(8):702-705.
[38] Takuwa N, Takuwa Y. Regulation of cell cycle molecules by the Ras effector system[J]. Mol Cell Endocrinol,2001 ,177(1-2):25-33.
[39] Aktas H, Cai H, Cooper GM. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1[J]. Mol Cell Biol,1997,17(7):3850-3857.
[40]宋鑫,曹亚.G 1/S检测点调控与癌变多阶段关系[J].国外医学·分子生物学分册,2002,24(2):73-76.
[41] Donnellan R,Chetty AR. Cyclin E in human cancers [J].FASEB,1999,13: 773-780.
[42]李长民,庄如锦,李佩玲,等. p27和cyclin E在宫颈癌中的表达及其临床意义[J].中国现代医学杂志,2005,15(11)1651-1654.
[43]韦毓,庞朗,冯秀英. PTEN、CyclinE与子宫内膜癌[J].柳州医学,2006,19(2):101-104.
[44] Rosen DG, Yang G, Deavers MT ,et al . Cyclin E Expression Is Correlated with Tumor Progression and Predicts a Poor Prognosis in Patients with Ovarian Carcinoma [J].Cancer, 2006,106 (9 )1925-1932.
[45]周奇,粱力建,彭宝岗,等.肝细胞癌中p27、cyclin E和cyclin A的表达及相关分析[J].中山大学学报(医学科学版) ,2006 ,27 (3S ):60-63.
[46]胃癌石玉宝,刘晓杰,李勇,等. CyelinE在胃癌中的表达及其与临床生物学行为关系的研究[J].现代肿瘤医学,2008,16(12 ):2113-2115.
[47]杨彦,王力,程若川.大肠癌中Cyc I i n E、p27的表达及意义[J].中华临床医药,2003 ,4 (23 ):32-35.
[48] Hui Y, ping YJ, Xin Z, et al. Expression of p57 k p2 and cyclinE proteins in human pancreatic cancer[J]. Chinese Medical ,2003,116(6):944-946.
[49] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Int J Cancer,2003, 104(3):369-375.
[50] Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles[J]. Oncogene,2005, 24:2776-2786.
[51] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[52]谢宛玉,马艳.宫颈癌P27蛋白、CyclinE蛋白表达的研究[J].美国中华临床医学杂志,2002 ,4 (1) 34-36.
[53] Pruitt K, Pestell RG, Der CJ. Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells[J ].Biol Chem,2000 ,275(52):40916-40924.
[54] Hitomi M , Stacey DW. Ras-dependent cell cycle commitment during G2 phase[J].FESB Lett,2001,490:123-131.
[55] Pruitt K, Pestell RG, Der CJ. Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells[J ].Biol Chem,2000 ,275(52):40916-40924.
[56] Hitomi M , Stacey DW . Ras-dependent cell cycle commitment during G2 phase[J].FESB Lett,2001,490:123-131.
[57] Jeong SN, Yoshinori I, Michiie S, et al.Ras Farnesylation Inhibitor FTI-277 Restores the E-Cadherin/Catenin Cell[J].Cancer Res,2002, 93(9):1020-1028.
[58] Prober DA, Edgar BA.Ras1 promotes cellular growth in the Drosophila wing[J]. Cell,2000, 100(4):435-446.
[59] Wingate H, Puskas A, Duong M, et al.Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression[J]. Cell Cycle, 2009,8(7):1062-1068.
[60] Mull BB, Cox J, Bui T, et al.Post-translational modification and stability of low molecular weight cyclin E[J].Oncogene,2009, 28(35):3167-3176.
[61] Kasahara K, Nakayama Y, Nakazato Y , et al.Src signaling regulates completion of abscission in cytokinesis through ERK/MAPK activation at the midbody[J]. Biol Chem,2007,282(8):5327-5339.
[62] ChristopherM. L,Christa BF,Vicente P, et al.Phosphatidylinositol 3-Kinase Inhibition by LY294002 Radiosensitizes Human Cervical Cancer Cell Lines[J].Cancer Res 2006,12(1):250-256.
[63] Wier?d L, Rosseland CM, Lindeman B, et al.CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes[J]. Cell Prolif, 2007,40(4):475-487.
[64] Gao N, Flynn DC, Zhang Z, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells[J]. Cell Physiol,2004,287(2):C281-C291.
[65] Hartwell LH, Mortimer RK, Culotti J, et al. Genetic control of the cell division cycle in yeast: V.genetic analysis of cdc mutants[J]. Genetics, 1973,74:267-286.
[66] Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans[J].Genetics, 1993,135:765-783 .
[67] Hubbard EJ, Wu G, Kitajewski J, et al. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins[J]. Genes Dev, 1997,11:3182-3193.
[68] Oberg C, Li JH, Pauley A, et al. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog[J]. Biol. Chem,2001,2 76:35847-35853 .
[69] Wu, G, Svetlana L, Indranil D,et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation[J].Cell. Biol,2001,21: 7403-7415 .
[70] Gupta-Rossi N, Le Bail O, Gonen H, Brou C, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor[J]. Biol. Chem, 2001,276:34371-34378 .
[71] Nakayama KI, Nakayama K. Ubiquitin ligases:cell-cycle control and cancer[J]. Nature Rev Cancer, 2006, 6:369-381.
[72] Yada M, Hatakeyama S, Kamura T, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7[J].EMBO,2004, 23(10):2116- 2125.
[73] Bonetti P, Davoli T, Sironi C, et al.Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma[J].Cell Biol,2008, 182:19-26.
[74] Nateri AS, Riera-Sans L, Da Costa C, et al. The ubiquitin ligase SCF Fbw7 antagonizes apoptotic JNK signaling [J]. Sci, 2004, 303(5662): 1374-1378.
[75] Anzi S, Finkin S, Shaulian E. Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV[J].Cell Signal,2008, 20:862-871.
[76] Wu G, Lyapina I, Das J, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation[J]. Cell Biol,2001, 21:7403-7415.
[77] O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors[J]. Exp Med,2007, 204:1813-1824.
[78] Kitagawa K, Hiramatsu Y, Uchida C, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb[J]. Oncogene,2009, 28:2393-2405.
[79] Welcker M, Clurman BE. Fbw7/hCDC4 dimerization regulates its substrate interactions[J]. Cell Div,2007,2,7.
[80] Mao JH, Perez-Losada J, Wu D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene[J]. Nature,2004,432:775-779.
[81] Welcker M, Orian A, Grim JA, et al. A Nucleolar Isoform of the Fbw7 Ubiquitin Ligase Regulates c-Myc and Cell Size[J].Cur Biol, 2004,14:1852-1857.
[82] Wei Z, Deanna MK. Fbw7 Isoform Interation Contributes to Cyclin E Proteolysis[J].Cancer Res,2006,4:935-943.
[83] Grim JE, Gustafson MP,Hirata RK, et al. Isoform-and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J].Cell Biol,2008,181:913-920.
[1] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer[J].Nat Rev Cancer ,2008, 8: 438-449.
[2] Nakayama KI, Nakayama K. Ubiquitin ligases:cell-cycle control and cancer[J]. Nature Rev Cancer, 2006, 6:369-381.
[3] Welcker M, Clurman BE. ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008, 8:83-93.
[4] Hartwell LH, Mortimer RK, Culotti J, et al. Genetic control of the cell division cycle in yeast: V.genetic analysis of cdc mutants[J]. Genetics, 1973,74:267-286.
[5] Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans[J].Genetics, 1993,135:765-783.
[6] Hubbard EJ, Wu G, Kitajewski J, et al. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins[J]. Genes Dev, 1997,11:3182-3193.
[7] Oberg C, Li JH, Pauley A, et al. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog[J].Biol. Chem,2001,276:35847-35853.
[8] Wu, G, Svetlana L, Indranil D,et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation[J].Cell. Biol,2001,21: 7403-7415.
[9] Gupta-Rossi N, Le Bail O, Gonen H, Brou C, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor[J]. Biol. Chem, 2001,276:34371-34378.
[10] Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer[J]. Cancer Res ,2002,62:4535-4539.
[11] Bai C, Sen P, Hofmann K, et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box[J]. Cell, 1996,86:263-274.
[12] Hao B, Oehlmann S, Sowa ME, et al. Structure of a Fbw7–Skp1–cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases[J]. Mol. Cell ,2007,26:131-143.
[13] Welcker M, Clurman BE. Fbw7/hCDC4 dimerization regulates its substrate interactions[J]. Cell Div,2007,2,7.
[14] Tang X, Orlicky S, Lin Z, et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination[J]. Cell, 2007,129:1165-1176.
[15] Zhang W, Koepp DM. Fbw7 isoform interaction contributes to cyclin E proteolysis[J]. Cancer Res,2006, 4:935-943.
[16] Kimura T, Gotoh M, Nakamura Y, et al. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53[J].Cancer Sci,2003,94:431-436.
[17] Welcker M, Orian A, Grim JE, et al. A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size[J]. Curr Biol, 2004,14:1852-1857.
[18] Ye, X, Nalepa G, Welcker M, et al. Recognition of phosphodegron motifs in human cyclin E by the SCFFbw7 ubiquitin ligase[J].Biol. Chem,2004,279: 50110-50119.
[19] Nash P, Tang X, Orlicky S, et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication[J]. Nature ,2001,414:514-521.
[20] Koepp DM, Schaefer LK, Ye X, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science, 2001, 294:173-177.
[21] Ekholm-Reed S, Spruck CH, Sangfelt O, et al. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer[J]. Cancer Res, 2004,64:795-800.
[22] Sangfelt O, Cepeda D, Malyukova A, et al. Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do not overexpress cyclin E[J].Cell Cycle,2008,7:1075-1082.
[23] Grim JE, Gustafson MP, Hirata RK, et al. Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J]. Cell Biol, 2008,181:913-920.
[24] Yada M, Hatakeyama S, Kamura T, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7[J].EMBO,2004, 23(10):2116-2125.
[25] Bonetti P, Davoli T, Sironi C, et al.Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma[J].Cell Biol,2008, 182:19-26.
[26] Nateri AS, Riera-Sans L, Da Costa C, et al. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling[J].Sci,2004,303(5662):1374-1378.
[27] Anzi S, Finkin S, Shaulian E. Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV[J].Cell Signal,2008, 20:862-871.
[28] Wu G, Lyapina I, Das J, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation[J]. Cell.Biol, 2001,21: 7403-7415.
[29] O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors[J]. Exp Med,2007, 204:1813-1824.
[30] Kitagawa K, Hiramatsu Y, Uchida C, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb[J]. Oncogene,2009, 28:2393-2405.
[31] Willmarth NE,Albertson DG,Ethier SP.Chromosomalinstability and lack of cyclin E regulation in hCdc4 mutanthuman breast cancer cells[J].Breast Cancer Res,2004,6:R531-539.
[32] Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene(CCNE) amplification and hCDC4 mutations in endometrial carcinoma[J].Pathol, 2003,201:589-595.
[33] Kwak EL, Moberg KH, Wahrer DC, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer[J].Gynecol Oncol, 2005,98:124-128.
[34] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7,AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003,163:1255-1260.
[35] Song JH, Schnittke N, Zaat A, et al. FBXW7 mutation in adult T-cell and B-cellacute lymphocytic leukemias[J]. Leuk Res,2008, 32:1751-1755.
[36] Thompson BJ, Jankovic V, Gao J, et al. Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7[J]. Exp Med,2008, 205:1395-1408.
[37] Mao JH, Perez-Losada J, Wu D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene[J]. Nature,2004,432:775-779.
[38] Erlandsson F, W?hlby C, Ekholm-Reed S, et al.Abnormal expression pattern of cyclin E in tumour cells[J]. Int J Cancer,2003, 104(3):369-375.
[39] Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles[J]. Oncogene,2005, 24:2776-2786.
[40] Park EA, Macalpine DM, Orr-Weaver TL. Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation[J]. Proc Natl Acad Sci,2007, 104(43):16739-16746.
[41] Spruck CH, Won KA, Reed SI.Deregulated cyclin E induces chromosome instability[J]. Nature, 1999,401(6750):297-300.
[42] Clurman BE, Sheaff RJ, Thress K, et al. Turnover of cyclin E by the ubiquitinproteasome pathway is regulated by cdk2 binding and cyclin phosphorylation[J]. Genes Dev,1996,10:1979-1990.
[43] Won KA, Reed SI. Activation of cyclinE/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E[J]. EMBO,1996, 15: 4182-4193.
[44] Strohmaier H, Spruck CH, Kaiser P, et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line[J].Nature, 2001,413:316-322.
[45] Moberg KH, Mukherjee A, Veraksa A, et al. The Drosophila F Box Protein Archipelago Regulates dMyc Protein Levels In Vivo[J].Curr. Biol,2004,14: 965-974.
[46] Koepp DM, Schaefer LK, Ye X,et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase[J]. Science,2001,294:173-177.
[47] Welcker M, Singer J, Loeb KR, et al. Multisite phosphorylation by Cdk2 and GSK3controls cyclin E degradation[J].Cell,2003,12:381-392.
[48] Welcker M,Clurman BE.FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation[J].Nat Rev Cancer,2008,8(2):83-93.
[49] Moberg KH, Bell DW, Wahrer DC, et al. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines[J]. Nature,2001,413: 311-316.
[50] Susanna ER, Spruck CH, Spruck R, et al. Mutation of hCDC4 Leads to Cell Cycle Deregulation of Cyclin E in cancer[J].Cancer Rescarch,2004,64: 795-800.
[51] Grandori C, Cowley SM, James LP, et al. The Myc/Max/Mad network and the transcriptional control of cell behavior[J]. Cell ,2000,16:653-699.
[52] Amati B. Myc degradation: dancing with ubiquitin ligases[J]. Sci, 2004,101:8843-8844.
[53] Angel P, Karin M. The role of jun,fos and the AP-1 complex in cell proliferation and transformation[J].Biochem Biophys Acta,1991,1072:129-159.
[54] Wei W, Jin J, Schlisio S, et al. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase[J]. Cancer Cell, 2005,8(1):25-33.
[55] Welcker M, Clurman BE.The SV40 Large T Antigen Contains a Decoy Phosphodegron That Mediates Its Interactions with Fbw7/hCdc4*[J]Biol Chem,2005,280(9):7654-7658.
[56] Lai, EC.. Protein degradation: four E3s for the Notch pathway[J]. Curr.Biol, 2002,12(2):74-78.
[57] Tetzlaff MT, Yu W, Li M, et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein[J]. Sci,2004,101: 3338-3345.
[58] Tsunematsu R, Nakayama K, Oike Y, et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development[J].Bio Chemistry, 2004, 279(10):9417-9423.
[59] Jung-Soon M, Mi-Yeon K, Seung-Ok H, et al. Integrin-Linked Kinase ControlsNotch1 Signaling by Down-Regulation of Protein Stability through Fbw7 Ubiquitin Ligase[J]. Cell. Biol, 2007,27: 5565-5574.
[60] Jennifer ON, Jonathan G, Peter S, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to -secretase inhibitors[J]. Exp. Med,2007, 204: 1813-1824.
[61] Rajagopalan H, Jallepalli PV, Rago C, et al. Inactivation of hCDC4 can cause chromosomal instability[J]. Nature,2004, 428(6978):77-81.
[62] Welcker M, Orian A, Grim JA, et al. A Nucleolar Isoform of the Fbw7 Ubiquitin Ligase Regulates c-Myc and Cell Size[J]. Cur Biol, 2004,14:1852-1857.
[63] Wei Z, Deanna MK. Fbw7 Isoform Interation Contributes to Cyclin E Proteolysis[J].Cancer Res,2006,4:935-943.
[64] Grim JE, Gustafson MP,Hirata RK, et al. Isoform-and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase[J].Cell Biol,2008,181:913-920.
[65] Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7)[J].Cell Cycle,2005, 4:1356-1359.
[66] Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets[J]. Pathol,2003, 163:1255-1260.