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系統識別號 U0026-3107201214235500
論文名稱(中文) Annexin A2對於肺癌細胞生長及壓力刺激下的角色
論文名稱(英文) The Role of Annexin A2 on Lung Cancer Cell Growth and Stress Response
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 王琪芸
研究生(英文) Chi-Yun Wang
學號 s58951455
學位類別 博士
語文別 英文
論文頁數 91頁
口試委員 口試委員-蘇五洲
口試委員-王憶卿
召集委員-林以行
口試委員-吳國瑞
口試委員-張俊彥
指導教授-林秋烽
中文關鍵字 ANXA2  肺癌  細胞週期  細胞增生  訊息傳遞 
英文關鍵字 ANXA2  Lung cancer  Cell cycle  Proliferation  Signal transduction 
學科別分類
中文摘要 ANXA2是一種鈣離子依賴性結合至細胞膜磷脂質的蛋白質,通常表現在細胞質中。當ANXA2和S100/A10形成複合體時則會表現在細胞膜表面。ANXA2參與在許多的細胞作用中,如細胞存活、生長、分裂及分化。缺乏ANXA2 表現會使細胞對於死亡刺激較為敏感。在許多種的癌症中,過度表現的ANXA2扮演促進腫瘤生成的角色,但是ANXA2在肺癌中的角色上不清楚。而且,關於本身ANXA2蛋白質表現調控及其對於細胞增生的調節作用並不清楚。本論文的第一部份將探討ANXA2在肺癌中的表現。將研究不同病程時期的臨床肺癌病人檢體中ANXA2蛋白質表現的程度差異,並將進一步探討ANXA2 在肺癌癌化機制上的可能作用以及對於肺癌病人預後的影響。研究結果發現,ANXA2會大量表現在肺癌上皮細胞上而且跟病人的預後有負相關。而且,在BALB/c裸鼠體內由A549所長成的腫瘤中,ANXA2 會持續表現在增生旺盛的腫瘤細胞膜周圍而非腫瘤中心的壞死的區域。本論文的第二部份將釐清ANXA2在肺癌細胞週期的進行及細胞增生機制上的可能作用。ANXA2在癌細胞增生扮演重要角色,然而ANXA2如何調控細胞週期機制尚不清楚。研究結果發現,當非小細胞肺癌細胞A549缺乏ANXA2並不會引起細胞毒殺死亡,但使活體內腫瘤生長及活體外細胞增生產生缺陷。降低ANXA2的表達會使細胞週期停滯於間期的G2 期。很意外地,降低ANXA2表達會使p53蛋白表達量增加,以及使p53下游基因表達隨之增加,並伴隨著p53相關的G2期停滯。在ANXA2缺乏的細胞中,JNK會去活化並伴隨著G2停滯以及細胞增生受到抑制。細胞內缺乏ANXA2會失去受JNK調控而穩定表現的c-Jun而使p53轉錄層級上的增加。這些結果證明一個ANXA2在肺癌細胞增生的新奇角色,ANXA2藉由維持JNK/c-Jun的訊號而抑制p53而促進細胞周期進行。本論文的第三部份將釐清ANXA2降解的調控機制及對肺癌細胞功能調節的可能影響。在此,我們證明了死亡刺激所誘導ANXA2裂解的可能的機制。研究證明,細胞內的ANXA2蛋白質會隨著死亡刺激時間增長而發生裂解。除了肺腺癌細胞,ANXA2蛋白裂解也發生在其他細胞中,包括類上皮細胞癌及子宮頸鱗狀上皮癌。在血清移除的模式下,Akt的活化被抑制接隨著GSK-3的活化,此過程中蛋白質去磷酸酶PP2A參與其中。我們發現 PP2A調節之GSK-3確實參與在ANXA2蛋白質裂解機制,但是如果只抑制PI3K/Akt的訊號卻不能造成ANXA2蛋白質裂解。這些結果顯示出PP2A的重要性。另外,我們發現serine 蛋白酶而非cathepsin可以造成ANXA2 蛋白質的裂解。進一步,我們發現PP2A和GSK-3 會透過調控Bax及Mcl-1在粒線體上的表現而導致ANXA2蛋白質的裂解。當粒線體膜完整性受破壞時,粒線體內的serine蛋白酶Omi/HtrA2就會被釋放到細胞質中因而導致ANXA2 的裂解。在生物功能方面,我們發現當抑制了GSK-3時,抗癌藥物cisplatin所引起的細胞死亡情形會被抑制。從這個計畫,我們發現在肺癌,ANXA2會過度表現。一旦降低ANXA2表現,會藉由調控JNK/c-Jun,導致p53所調節的G2期抑制。在壓力刺激之下,GSK-3及Omi/HtrA2協同性地造成ANXA2降解而使細胞走向死亡。
英文摘要 ANXA2, a calcium-dependent phospholipid binding protein, is widely expressed in cytoplasm and on the cell surface membrane while complexed with S100/A10. ANXA2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of ANXA2 makes cells more sensitive to apoptotic stimuli. ANXA2 is overexpressed in many kinds of cancer and promotes tumorigenesis; however, the role of ANXA2 in lung cancer tumorigenesis has not been determined. This thesis is aimed at understanding the expression level of ANXA2 and the role of ANXA2 in lung tumorigenesis and further the regulatory mechanism of ANXA2 under stress. In the first part of this thesis, the expression of ANXA2 in patients with non-small cell lung cancer (NSCLC) was detected. Results show that ANXA2 is richly expressed in non-small cell lung cancer (NSCLC) and is positively correlated with poor prognosis. The survival time of patients with lower-ANXA2-expressed lung cancer is longer than whom with higher-ANXA2-expressed lung cancer. Moreover, ANXA2 is persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma A549 cell-derived tumor. In the second part of this thesis, the regulatory role of ANXA2 on cell cycle progression and cell proliferation was clarified. ANXA2 plays an important role in cancer cell proliferation, whereas the molecular mechanisms underlying the ANXA2-regulated cell cycle are still unknown. Results show that NSCLC A549 cells lacking ANXA2 exhibits defects in tumor growth in vivo and cell proliferation in vitro without cytotoxicity. ANXA2 knockdown induces cell cycle arrest at the G2 phase of interphase. Unexpectedly, ANXA2 silencing increases the expression of p53 and its downstream genes followed by a partial p53-mediated G2 arrest. Aberrant c-Jun N-terminal kinase (JNK) inactivation, which is observed in ANXA2 deficient cells, causes cell proliferation inhibition following G2 arrest. A lack of ANXA2 causes a loss of JNK-regulated c-Jun expression followed by a p53 transcriptional increase. These results demonstrate a novel role of ANXA2 in NSCLC cell proliferation by facilitating the cell cycle through the maintenance of JNK/c-Jun-inhibited p53. Further, the regulation of ANXA2 expression is still unclear. In the final part of this thesis, the regulation of ANXA2 expression was clarified under apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced ANXA2 cleavage. Results show that, under apoptotic stimuli, ANXA2 is cleaved via a time-dependent manner. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated GSK-3 is essential for this process. Therefore, inhibiting GSK-3 reverses serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocks apoptotic stimuli-induced ANXA2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, causes ANXA2 cleavage via an Omi/HtrA2-dependent pathway. These results demonstrate that GSK-3 and Omi/HtrA2 synergistically cause ANXA2 cleavage and then cell cycle inhibition or apoptosis. Taken together, ANXA2 is overexpressed in lung cancer and loss of ANXA2 mediates p53 suppression of G2/M progression by targeting JNK/c-Jun. Under stress, GSK-3 and Omi/HtrA2 synergistically cause ANXA2 downregulation following cell apoptosis.
論文目次 Table of Contents
Abstract I
中文摘要 III
誌謝 V
Table of Contents VI
Table List IX
Figure List X
Abbreviation XII
Chapter 1 Introduction 1
1-1 ANXA2 1
1-1-1 Characterization of ANXA2 1
1-1-2 Physiological Function of ANXA2 2
1-1-3 Functional Regulation of ANXA2—Post-translational modification 3
1-1-4 The Importance of ANXA2 N-terminus 3
1-1-5 The role of ANXA2 in tumorigenesis 4
1-2 An overview of the cell cycle 11
1-2-1 Cell cycle control system 11
1-2-2 G2/M checkpoints 11
1-2-3 Contribution of p53 to G2 Arrest 12
1-3 Lung cancer 13
Chapter 2 Objective and Specific aims 14
Chapter 3 Materials and Methods 15
3-1 Cell Culture and Reagents 15
3-2 Animals and Xnograft Models 16
3-3 Tissue Collection 16
3-4 Western Blot Analysis 17
3-5 RT-PCR Analysis 17
3-6 Real-time qRT-PCR 18
3-7 Short Interfering RNA (siRNA) Preparation and Gene Expression 18
3-8 Lentiviral-based RNA Interference (RNAi) Transfection 19
3-9 Cell Cycle Analysis 20
3-10 Mitochondrial Functional Assay 20
3-11 Immunostaining 20
3-12 Immunohistochemistry 22
3-13 Colony Formation Assay 22
3-14 WST-8 Assay 23
3-15 LDH Assay 23
3-16 Microarray 23
3-17 Chromatin Immunoprecipitation (ChIP) 24
3-18 Statistical Analysis 24
Chapter 4 Results 26
4-1 To investigate the expression of ANXA2 in mice and patients with NSCLC 26
4-1-1 ANXA2 overexpression in lung cancers predicts poor survival in patients with NSCLC 26
4-1-2 ANXA2 expression is involved in cell proliferation and survival 26
4-2 To investigate the role of ANXA2 in lung tumorigenesis 27
4-2-1 ANXA2 knockdown causes defects in A549 cell-derived tumor growth in vivo and A549 cell proliferation in vitro 27
4-2-2 ANXA2 silencing induces cell cycle arrest at G2 phase partially in a p53-regulated manner 28
4-2-3 JNK is inactivated by ANXA2 deficiency 29
4-2-4 ANXA2 silencing attenuates JNK/c-Jun-regulated p53 suppression transcriptionally 30
4-3 To clarify the regulatory mechanisms for ANXA2 expression 31
4-3-1 Apoptotic stimuli causes ANXA2 cleavage in human epithelial cells 31
4-3-2 GSK-3 is essential for ANXA2 cleavage with apoptotic stimuli 31
4-3-3 PP2A-triggered Akt inactivation, followed by GSK-3 activation, and contributes to apoptotic stimuli-induced ANXA2 cleavage 32
4-3-4 Serine proteases but not cathepsins are involved in apoptotic stimuli-induced ANXA2 cleavage 33
4-3-5 Bax activation and Mcl-1 degradation are involved in serum withdrawal-induced ANXA2 cleavage 33
4-3-6 Mitochondrial serine protease Omi/HtrA2 is involved in apoptotic stimuli-induced ANXA2 cleavage 34
Chapter 5 Conclusion 36
Chapter 6 Discussion 37
6-1 For the expression of ANXA2 and the role of ANXA2 in NSCLC tumorigenesis 37
6-1-1 The role of ANXA2 in tumor cell proliferation and its therapeutic implication 37
6-1-2 The mechanism of JNK/c-Jun on negatively regulating p53 expression 38
6-1-3 ANXA2 also mediates p53-independent G2/M arrest 39
6-1-4 Mechanisms for JNK regulation 39
6-1-5 Possible mechanism for ANXA2-mediated JNK activation 40
6-1-6 The role of p11 in tumor cell proliferation 41
6-2 For the mechanism of apoptotic stimuli-induced ANXA2 cleavage 41
6-2-1 Mechanism of ANXA2 dowregulation 42
6-2-2 Contribution of Bcl-2 family proteins and mitochondrial proteins to ANXA2 cleavage 43
6-2-3 Regulation of Bcl-2 family protein by PP2A and GSK-3 43
6-2-4 The possible biological function of ANXA2 44
Chapter 7 References 46
Table 56
Figures 59
Appendix 81
Curriculum Vitae 88
參考文獻 References
Albain, K. S., Swann, R. S., Rusch, V. W., Turrisi, A. T., 3rd, Shepherd, F. A., Smith, C., Chen, Y., Livingston, R. B., Feins, R. H., Gandara, D. R., Fry, W. A., Darling, G., Johnson, D. H., Green, M. R., Miller, R. C., Ley, J., Sause, W. T., and Cox, J. D. (2009) Lancet 374(9687), 379-386
Babiychuk, E. B., and Draeger, A. (2000) The Journal of cell biology 150(5), 1113-1124
Babiychuk, E. B., Monastyrskaya, K., Burkhard, F. C., Wray, S., and Draeger, A. (2002) Faseb J 16(10), 1177-1184
Bao, H., Jiang, M., Zhu, M., Sheng, F., Ruan, J., and Ruan, C. (2009) International journal of hematology 90(2), 177-185
Booher, R. N., Holman, P. S., and Fattaey, A. (1997) The Journal of biological chemistry 272(35), 22300-22306
Braden, A. R., Kafka, M. T., Cunningham, L., Jones, H., and Vishwanatha, J. K. (2009) Journal of nanoscience and nanotechnology 9(5), 2856-2865
Brambilla, E., Travis, W. D., Colby, T. V., Corrin, B., and Shimosato, Y. (2001) Eur Respir J 18(6), 1059-1068
Brichory, F. M., Misek, D. E., Yim, A. M., Krause, M. C., Giordano, T. J., Beer, D. G., and Hanash, S. M. (2001) Proc Natl Acad Sci U S A 98(17), 9824-9829
Bruce Alberts, A. J., Julian Lewis, Martin Raff, Keith Roberts, Peter walter. (2002) Molecular biology of the cell, 4th ed. Ed., Garland Science, New York
Brumby, A. M., Goulding, K. R., Schlosser, T., Loi, S., Galea, R., Khoo, P., Bolden, J. E., Aigaki, T., Humbert, P. O., and Richardson, H. E. (2011) Genetics 188(1), 105-125
Camors, E., Monceau, V., and Charlemagne, D. (2005) Cardiovascular research 65(4), 793-802
Cesarman, G. M., Guevara, C. A., and Hajjar, K. A. (1994) The Journal of biological chemistry 269(33), 21198-21203
Chen, J., Martin, B. L., and Brautigan, D. L. (1992) Science (New York, N.Y 257(5074), 1261-1264
Chen, J., Parsons, S., and Brautigan, D. L. (1994) The Journal of biological chemistry 269(11), 7957-7962
Chetcuti, A., Margan, S. H., Russell, P., Mann, S., Millar, D. S., Clark, S. J., Rogers, J., Handelsman, D. J., and Dong, Q. (2001) Cancer Res 61(17), 6331-6334
Chiang, Y., Davis, R. G., and Vishwanatha, J. K. (1996) Biochim Biophys Acta 1313(3), 295-301
Chiang, Y., Rizzino, A., Sibenaller, Z. A., Wold, M. S., and Vishwanatha, J. K. (1999) Mol Cell Biochem 199(1-2), 139-147
Choi, K. S., Fitzpatrick, S. L., Filipenko, N. R., Fogg, D. K., Kassam, G., Magliocco, A. M., and Waisman, D. M. (2001) The Journal of biological chemistry 276(27), 25212-25221
Choi, K. S., Fogg, D. K., Yoon, C. S., and Waisman, D. M. (2003) Faseb J 17(2), 235-246
Cole, S. P., Pinkoski, M. J., Bhardwaj, G., Deeley, R. G., Sinha, P., Hutter, G., Kottgen, E., Dietel, M., Schadendorf, D., Lage, H., Han, E. K., Tahir, S. K., Cherian, S. P., Collins, N., Ng, S. C., Wang, Y., Serfass, L., Roy, M. O., Wong, J., Bonneau, A. M., Georges, E., Zhang, F., Zhang, L., Zhang, B., Wei, X., Yang, Y., Qi, R. Z., Ying, G., Zhang, N., Niu, R., Zhu, F., Wang, Y., Zeng, S., Fu, X., Wang, L., and Cao, J. (1992) British journal of cancer 65(4), 498-502
Cuervo, A. M., Gomes, A. V., Barnes, J. A., and Dice, J. F. (2000) The Journal of biological chemistry 275(43), 33329-33335
Das, M., Jiang, F., Sluss, H. K., Zhang, C., Shokat, K. M., Flavell, R. A., and Davis, R. J. (2007) Proceedings of the National Academy of Sciences of the United States of America 104(40), 15759-15764
Dennis, G., Jr., Sherman, B. T., Hosack, D. A., Yang, J., Gao, W., Lane, H. C., and Lempicki, R. A. (2003) Genome biology 4(5), P3
Diaz, V. M., Hurtado, M., Thomson, T. M., Reventos, J., and Paciucci, R. (2004) Gut 53(7), 993-1000
Draetta, G., and Eckstein, J. (1997) Biochimica et biophysica acta 1332(2), M53-63
Dubois, T., Oudinet, J. P., Russo-Marie, F., and Rothhut, B. (1995) Biochem J 310(Pt 1), 243-248
Eferl, R., Ricci, R., Kenner, L., Zenz, R., David, J. P., Rath, M., and Wagner, E. F. (2003) Cell 112(2), 181-192
Emans, N., Gorvel, J. P., Walter, C., Gerke, V., Kellner, R., Griffiths, G., and Gruenberg, J. (1993) The Journal of cell biology 120(6), 1357-1369
Emoto, K., Sawada, H., Yamada, Y., Fujimoto, H., Takahama, Y., Ueno, M., Takayama, T., Uchida, H., Kamada, K., Naito, A., Hirao, S., and Nakajima, Y. (2001a) Anticancer research 21(2B), 1339-1345
Emoto, K., Yamada, Y., Sawada, H., Fujimoto, H., Ueno, M., Takayama, T., Kamada, K., Naito, A., Hirao, S., and Nakajima, Y. (2001b) Cancer 92(6), 1419-1426
Esposito, I., Penzel, R., Chaib-Harrireche, M., Barcena, U., Bergmann, F., Riedl, S., Kayed, H., Giese, N., Kleeff, J., Friess, H., and Schirmacher, P. (2006) The Journal of pathology 208(5), 673-685
Fan, X., Krahling, S., Smith, D., Williamson, P., and Schlegel, R. A. (2004) Molecular biology of the cell 15(6), 2863-2872
Feigenberg, S. J., Hanlon, A. L., Langer, C., Goldberg, M., Nicolaou, N., Millenson, M., Coia, L. R., Lanciano, R., and Movsas, B. (2007) J Thorac Oncol 2(4), 287-292
Filipenko, N. R., and Waisman, D. M. (2001) J Biol Chem 276(7), 5310-5315
Frank, G. D., Motley, E. D., Inagami, T., and Eguchi, S. (2000) Biochem Biophys Res Commun 270(3), 761-765
Fritsche, M., Haessler, C., and Brandner, G. (1993) Oncogene 8(2), 307-318
Gerke, V., Creutz, C. E., and Moss, S. E. (2005) Nature reviews 6(6), 449-461
Gerke, V., and Moss, S. E. (1997) Biochimica et biophysica acta 1357(2), 129-154
Gerke, V., and Moss, S. E. (2002) Physiological reviews 82(2), 331-371
Germain, M., Milburn, J., and Duronio, V. (2008) The Journal of biological chemistry 283(10), 6384-6392
Gillette, J. M., Chan, D. C., and Nielsen-Preiss, S. M. (2004) J Cell Biochem 92(4), 820-832
Giono, L. E., and Manfredi, J. J. (2006) Journal of cellular physiology 209(1), 13-20
Greenberg, A. K., Basu, S., Hu, J., Yie, T. A., Tchou-Wong, K. M., Rom, W. N., and Lee, T. C. (2002) Am J Respir Cell Mol Biol 26(5), 558-564
Guzman-Aranguez, A., Olmo, N., Turnay, J., Lecona, E., Perez-Ramos, P., Lopez de Silanes, I., and Lizarbe, M. A. (2005) J Cell Biochem 94(1), 178-193
Hajjar, K. A., Jacovina, A. T., and Chacko, J. (1994) The Journal of biological chemistry 269(33), 21191-21197
Hajjar, K. A., and Krishnan, S. (1999) Trends Cardiovasc Med 9(5), 128-138
Halfter, U. M., Derbyshire, Z. E., and Vaillancourt, R. R. (2005) The Biochemical journal 388(Pt 1), 17-28
Han, J., Goldstein, L. A., Gastman, B. R., and Rabinowich, H. (2006) The Journal of biological chemistry 281(15), 10153-10163
Hansen, M. D., Ehrlich, J. S., and Nelson, W. J. (2002) The Journal of biological chemistry 277(47), 45371-45376
Hartwell, L. H., and Kastan, M. B. (1994) Science (New York, N.Y 266(5192), 1821-1828
He, K. L., Deora, A. B., Xiong, H., Ling, Q., Weksler, B. B., Niesvizky, R., and Hajjar, K. A. (2008) The Journal of biological chemistry 283(28), 19192-19200
Hollander, M. C., Maier, C. R., Hobbs, E. A., Ashmore, A. R., Linnoila, R. I., and Dennis, P. A. (2011) Oncogene 30(15), 1812-1821
Hollstein, M., and Hainaut, P. (2010) The Journal of pathology 220(2), 164-173
Huang da, W., Sherman, B. T., and Lempicki, R. A. (2009) Nature protocols 4(1), 44-57
Huang, P., Han, J., and Hui, L. (2010) Protein Cell 1(3), 218-226
Huang, Y., Jin, Y., Yan, C. H., Yu, Y., Bai, J., Chen, F., Zhao, Y. Z., and Fu, S. B. (2008) Molecular and cellular biochemistry 309(1-2), 117-123
Huang, Y., Yan, C. H., and Fu, S. B. (2005) Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22(6), 661-664
Hubaishy, I., Jones, P. G., Bjorge, J., Bellagamba, C., Fitzpatrick, S., Fujita, D. J., and Waisman, D. M. (1995) Biochemistry 34(44), 14527-14534
Huebner, K., Cannizzaro, L. A., Frey, A. Z., Hecht, B. K., Hecht, F., Croce, C. M., and Wallner, B. P. (1988) Oncogene research 2(4), 299-310
Inanami, O., Ohta, T., Ito, S., and Kuwabara, M. (1999) Antioxidants & redox signaling 1(4), 501-508
Inokuchi, J., Narula, N., Yee, D. S., Skarecky, D. W., Lau, A., Ornstein, D. K., and Tyson, D. R. (2009) International journal of cancer 124(1), 68-74
Jascur, T., Brickner, H., Salles-Passador, I., Barbier, V., El Khissiin, A., Smith, B., Fotedar, R., and Fotedar, A. (2005) Molecular cell 17(2), 237-249
Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C., and Thun, M. J. (2006) CA: a cancer journal for clinicians 56(2), 106-130
Ji, N. Y., Park, M. Y., Kang, Y. H., Lee, C. I., Kim, D. G., Yeom, Y. I., Jang, Y. J., Myung, P. K., Kim, J. W., Lee, H. G., Kim, J. W., Lee, K., and Song, E. Y. (2009) International journal of molecular medicine 24(6), 765-771
Johnsson, N., Marriott, G., and Weber, K. (1988) Embo J 7(8), 2435-2442
Johnstone, S. A., Hubaishy, I., and Waisman, D. M. (1992) J Biol Chem 267(36), 25976-25981
Kassam, G., Le, B. H., Choi, K. S., Kang, H. M., Fitzpatrick, S. L., Louie, P., and Waisman, D. M. (1998) Biochemistry 37(48), 16958-16966
Kassam, G., Manro, A., Braat, C. E., Louie, P., Fitzpatrick, S. L., and Waisman, D. M. (1997) J Biol Chem 272(24), 15093-15100
Khatlani, T. S., Wislez, M., Sun, M., Srinivas, H., Iwanaga, K., Ma, L., Hanna, A. E., Liu, D., Girard, L., Kim, Y. H., Pollack, J. R., Minna, J. D., Wistuba, II, and Kurie, J. M. (2007) Oncogene 26(18), 2658-2666
Kruse, J. P., and Gu, W. (2009) Cell 137(4), 609-622
Kumble, K. D., Iversen, P. L., and Vishwanatha, J. K. (1992) Journal of cell science 101, 35-41
Kumble, K. D., and Vishwanatha, J. K. (1991) Journal of cell science 99 ( Pt 4), 751-758
Kuwana, T., and Newmeyer, D. D. (2003) Current opinion in cell biology 15(6), 691-699
Langfort, R. (2010) Pneumonol Alergol Pol 78(6), 379-383
Laumonnier, Y., Syrovets, T., Burysek, L., and Simmet, T. (2006) Blood 107(8), 3342-3349
Lin, C. F., Chen, C. L., Chiang, C. W., Jan, M. S., Huang, W. C., and Lin, Y. S. (2007) Journal of cell science 120(Pt 16), 2935-2943
Linseman, D. A., Butts, B. D., Precht, T. A., Phelps, R. A., Le, S. S., Laessig, T. A., Bouchard, R. J., Florez-McClure, M. L., and Heidenreich, K. A. (2004) J Neurosci 24(44), 9993-10002
Liu, F., Stanton, J. J., Wu, Z., and Piwnica-Worms, H. (1997) Mol Cell Biol 17(2), 571-583
Liu, J., Rothermund, C. A., Ayala-Sanmartin, J., and Vishwanatha, J. K. (2003a) BMC biochemistry 4, 10
Liu, J. W., Shen, J. J., Tanzillo-Swarts, A., Bhatia, B., Maldonado, C. M., Person, M. D., Lau, S. S., and Tang, D. G. (2003b) Oncogene 22(10), 1475-1485
Liu, S. L., Lin, X., Shi, D. Y., Cheng, J., Wu, C. Q., and Zhang, Y. D. (2002) Archives of biochemistry and biophysics 406(2), 173-182
Liu, Y., Wang, Z., Jiang, M., Dai, L., Zhang, W., Wu, D., and Ruan, C. (2011) Leuk Res 35(7), 879-884
Longerich, T., Haller, M. T., Mogler, C., Aulmann, S., Lohmann, V., Schirmacher, P., and Brand, K. (2011) Pathology, research and practice 207(1), 8-14
Luk, C., Tsao, M. S., Bayani, J., Shepherd, F., and Squire, J. A. (2001) Cancer Genet Cytogenet 125(2), 87-99
Lukas, J., Lukas, C., and Bartek, J. (2004) DNA repair 3(8-9), 997-1007
Mai, J., Finley, R. L., Jr., Waisman, D. M., and Sloane, B. F. (2000) The Journal of biological chemistry 275(17), 12806-12812
Matsukawa, J., Matsuzawa, A., Takeda, K., and Ichijo, H. (2004) Journal of biochemistry 136(3), 261-265
Matsunaga, T., Inaba, T., Matsui, H., Okuya, M., Miyajima, A., Inukai, T., Funabiki, T., Endo, M., Look, A. T., and Kurosawa, H. (2004) Blood 103(8), 3185-3191
Maurer, U., Charvet, C., Wagman, A. S., Dejardin, E., and Green, D. R. (2006) Molecular cell 21(6), 749-760
Menell, J. S., Cesarman, G. M., Jacovina, A. T., McLaughlin, M. A., Lev, E. A., and Hajjar, K. A. (1999) The New England journal of medicine 340(13), 994-1004
Minden, A., Lin, A., Claret, F. X., Abo, A., and Karin, M. (1995) Cell 81(7), 1147-1157
Mishra, R., Barthwal, M. K., Sondarva, G., Rana, B., Wong, L., Chatterjee, M., Woodgett, J. R., and Rana, A. (2007) The Journal of biological chemistry 282(42), 30393-30405
Mohammad, H. S., Kurokohchi, K., Yoneyama, H., Tokuda, M., Morishita, A., Jian, G., Shi, L., Murota, M., Tani, J., Kato, K., Miyoshi, H., Deguchi, A., Himoto, T., Usuki, H., Wakabayashi, H., Izuishi, K., Suzuki, Y., Iwama, H., Deguchi, K., Uchida, N., Sabet, E. A., Arafa, U. A., Hassan, A. T., El-Sayed, A. A., and Masaki, T. (2008) International journal of oncology 33(6), 1157-1163
Morel, E., and Gruenberg, J. (2007) PLoS ONE 2(10), e1118
Mussunoor, S., and Murray, G. I. (2008) The Journal of pathology 216(2), 131-140
Nedjadi, T., Kitteringham, N., Campbell, F., Jenkins, R. E., Park, B. K., Navarro, P., Ashcroft, F., Tepikin, A., Neoptolemos, J. P., and Costello, E. (2009) Br J Cancer 101(7), 1145-1154
Ohno, Y., Izumi, M., Kawamura, T., Nishimura, T., Mukai, K., and Tachibana, M. (2009) Br J Cancer 101(2), 287-294
Oliferenko, S., Paiha, K., Harder, T., Gerke, V., Schwarzler, C., Schwarz, H., Beug, H., Gunthert, U., and Huber, L. A. (1999) The Journal of cell biology 146(4), 843-854
Paciucci, R., Tora, M., Diaz, V. M., and Real, F. X. (1998) Oncogene 16(5), 625-633
Parker, L. L., and Piwnica-Worms, H. (1992) Science (New York, N.Y 257(5078), 1955-1957
Petersson, S., Shubbar, E., Enerback, L., and Enerback, C. (2009) Melanoma research 19(4), 215-225
Pines, J. (1995) The Biochemical journal 308 ( Pt 3), 697-711
Raynal, P., and Pollard, H. B. (1994) Biochimica et biophysica acta 1197(1), 63-93
Rodrigo, J. P., Lequerica-Fernandez, P., Rosado, P., Allonca, E., Garcia-Pedrero, J. M., and de Vicente, J. C. (2011) Head & neck 33(12), 1708-1714
Roseman, B. J., Bollen, A., Hsu, J., Lamborn, K., and Israel, M. A. (1994) Oncology research 6(12), 561-567
Saelens, X., Festjens, N., Vande Walle, L., van Gurp, M., van Loo, G., and Vandenabeele, P. (2004) Oncogene 23(16), 2861-2874
Sarafian, T., Pradel, L. A., Henry, J. P., Aunis, D., and Bader, M. F. (1991) J Cell Biol 114(6), 1135-1147
Sasaki, K., Tsuno, N. H., Sunami, E., Tsurita, G., Kawai, K., Okaji, Y., Nishikawa, T., Shuno, Y., Hongo, K., Hiyoshi, M., Kaneko, M., Kitayama, J., Takahashi, K., and Nagawa, H. (2010) BMC Cancer 10, 370-381
Sato, M., Shames, D. S., Gazdar, A. F., and Minna, J. D. (2007) J Thorac Oncol 2(4), 327-343
Schreiber, M., Kolbus, A., Piu, F., Szabowski, A., Mohle-Steinlein, U., Tian, J., Karin, M., Angel, P., and Wagner, E. F. (1999) Genes & development 13(5), 607-619
Shang, L., Zhou, H., Xia, Y., Wang, H., Gao, G., Chen, B., Liu, Q., Shao, C., and Gong, Y. (2009) J Cell Mol Med 13(10), 4176-4184
Sharma, M. R., Koltowski, L., Ownbey, R. T., Tuszynski, G. P., and Sharma, M. C. (2006a) Exp Mol Pathol
Sharma, M. R., Koltowski, L., Ownbey, R. T., Tuszynski, G. P., and Sharma, M. C. (2006b) Exp Mol Pathol 81(2), 146-156
Sharma, M. R., Rothman, V., Tuszynski, G. P., and Sharma, M. C. (2006c) Exp Mol Pathol 81(2), 136-145
Shiozawa, Y., Havens, A. M., Jung, Y., Ziegler, A. M., Pedersen, E. A., Wang, J., Wang, J., Lu, G., Roodman, G. D., Loberg, R. D., Pienta, K. J., and Taichman, R. S. (2008) Journal of cellular biochemistry 105(2), 370-380
Singh, P., Wu, H., Clark, C., and Owlia, A. (2007) Oncogene 26(3), 425-440
Singh, T. K., Abonyo, B., Narasaraju, T. A., and Liu, L. (2004) Cellular signalling 16(1), 63-70
Stark, G. R., and Taylor, W. R. (2006) Mol Biotechnol 32(3), 227-248
Stepniak, E., Ricci, R., Eferl, R., Sumara, G., Sumara, I., Rath, M., Hui, L., and Wagner, E. F. (2006) Genes & development 20(16), 2306-2314
Sun, S., Schiller, J. H., Spinola, M., and Minna, J. D. (2007) The Journal of clinical investigation 117(10), 2740-2750
Tanaka, T., Akatsuka, S., Ozeki, M., Shirase, T., Hiai, H., and Toyokuni, S. (2004) Oncogene 23(22), 3980-3989
Tatenhorst, L., Rescher, U., Gerke, V., and Paulus, W. (2006) Neuropathol Appl Neurobiol 32(3), 271-277
Taylor, W. R., and Stark, G. R. (2001) Oncogene 20(15), 1803-1815
Teramoto, H., Coso, O. A., Miyata, H., Igishi, T., Miki, T., Gutkind, J. S., Minden, A., Lin, A., Claret, F. X., Abo, A., and Karin, M. (1996) The Journal of biological chemistry 271(44), 27225-27228
Tokiwa, G., Dikic, I., Lev, S., and Schlessinger, J. (1996) Science (New York, N.Y 273(5276), 792-794
Treier, M., Staszewski, L. M., and Bohmann, D. (1994) Cell 78(5), 787-798
Vishwanatha, J. K., Chiang, Y., Kumble, K. D., Hollingsworth, M. A., and Pour, P. M. (1993) Carcinogenesis 14(12), 2575-2579
Vishwanatha, J. K., Jindal, H. K., and Davis, R. G. (1992) Journal of cell science 101, 25-34
Vishwanatha, J. K., and Kumble, S. (1993) Journal of cell science 105, 533-540
Wagner, E. F., and Nebreda, A. R. (2009) Nat Rev Cancer 9(8), 537-549
Waisman, D. M. (1995) Molecular and cellular biochemistry 149-150, 301-322
Wang, C. Y., Lin, Y. S., Su, W. C., Chen, C. L., and Lin, C. F. (2009) Molecular biology of the cell 20(19), 4153-4161
Wang, T., Nelson, R. A., Bogardus, A., and Grannis, F. W., Jr. (2010) Cancer 116(6), 1518-1525
Wang, Y. X., Lv, H., Li, Z. X., Li, C., and Wu, X. Y. (2011) Pathol Oncol Res 18(2), 183-190
Warnes, G. R., Bolker, B., and Lumley, T. (2009) R package version 2(4)
Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R., and Chandel, N. S. (2010) Proceedings of the National Academy of Sciences of the United States of America 107(19), 8788-8793
Win, T., Sharples, L., Groves, A. M., Ritchie, A. J., Wells, F. C., and Laroche, C. M. (2008) Lung 186(2), 97-102
Xiao, L., and Lang, W. (2000) Cancer research 60(2), 400-408
Xin, M., and Deng, X. (2006) The Journal of biological chemistry 281(27), 18859-18867
Yamaguchi, H., Bhalla, K., and Wang, H. G. (2003) Cancer research 63(7), 1483-1489
Yang, Q. H., Church-Hajduk, R., Ren, J., Newton, M. L., and Du, C. (2003) Genes & development 17(12), 1487-1496
Yang, X., Popescu, N. C., and Zimonjic, D. B. (2011) Cancer research 71(8), 2916-2925
Zhang, J., Guo, B., Zhang, Y., Cao, J., and Chen, T. (2010a) Saudi medical journal 31(4), 374-381
Zhang, J., Guo, B., Zhang, Y., Cao, J., and Chen, T. (2010b) Saudi medical journal 31(4), 374-381
Zhang, S., Qiu, X., Gu, Y., and Wang, E. (2008) Lung cancer (Amsterdam, Netherlands) 62(3), 295-301
Zhang, X., Zhi, H. Y., Zhang, J., Wang, X. Q., Zhou, C. N., Wu, M., Sun, Y. T., and Liu, Z. H. (2003) Zhonghua zhong liu za zhi [Chinese journal of oncology] 25(4), 353-355
Zhao, P., Zhang, W., Tang, J., Ma, X. K., Dai, J. Y., Li, Y., Jiang, J. L., Zhang, S. H., and Chen, Z. N. (2010) Cancer Sci 101(2), 387-395

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