人垂体瘤转化基因（hPTTG）的调节机制及功能研究
摘要
恶性肿瘤是一类极其复杂的疾病，具有以下基本特征：细胞周期紊乱，有丝分裂异常，细胞具有基因组不稳定性。因此，从某种意义上来说，恶性肿瘤是一类细胞周期疾病。
人垂体瘤转化基因hPTTG，又称Securin，是有丝分裂中期纺锤体检验点通路的重要成员。它监控细胞周期的有序进行，保障细胞分裂的忠实性和遗传的稳定性，并且参与恶性转化和肿瘤发生。我们克隆表达了hPTTG基因，发现它影响细胞周期、促进细胞生长、引起恶性转化。我们使用RT-PCR和原位杂交方法，在食管癌中检测到hPTTG的高表达，统计学分析表明hPTTG的高表达与肿瘤的分化和转移密切相关。进一步深入研究hPTTG的调节机制，发现β-catenin／TCF通路上调hPTTG的转录和表达，并且食管癌标本的检测证明β-catenin的胞浆累积与hPTTG的高表达正相关；此外，MAPK通路抑制剂可抑制hPTTG的转录和表达；γ-synuclein引起染色体不稳定性并上调hPTTG的表达，hPTTG可能参与γ-synuclein引起不稳定性的过程。hPTTG广泛地影响一些重要的肿瘤相关基因，它上调癌基因cyclinD1和抗凋亡基因survivin的表达，抑制Gsk3β的激酶活性，并与p53结合。
综上所述，hPTTG的功能极其复杂，它参与细胞周期调控，沟通庞大的信号通路网络。探讨和阐明它参与肿瘤发生发展的作用机制，不仅对深入认识细胞周期和人类肿瘤大有裨益，还具有潜在的临床应用前景。
The malignant tumor is a complicated disease characterized with inordinate cell cycle, abnormal mitosis and genetic instability. In a certain sense, the malignant tumor is a kind of cell cycle diseases.
Human pituitary tumor transforming gene (hPTTG), also termed as Securin, is a key molecular of mitotic spindle checkpoint pathway. hPTTG surveilles orderly progression of cell cycle, ensures the fidelity of cell division and genetic stability, and participates in malignant transformation and tumorigenesis. We cloned and expressed hPTTG, observed its influences on cell cycle, and found that it accelerated cell proliferation and promoted cell malignant transformation. We detected its overexpression in human esophageal tumor tissues compared with the corresponding normal tissues, by using RT-PCR assay and in situ hybridization. On the other hand, the statistical analysis revealed that overexpression of hPTTG was closely associated with tumor differentiation and lymph node metastasis. We further investigated hPTTG's regulation mechanisms, demonstrated that β-catenin/TCF up-regulated hPTTG transcriptional avtivity and its expression. Subsequently, we detected the positive correlation between cytoplasmic accumulation of β-catenin and overexpression of hPTTG in 69 human esophageal tumors. Furthermore, the inhibitors of MAPK pathway could depress hPTTG's transcriptional activity and its expression, indicating that MAPK pathway may regulate hPTTG. We also found that γ-synuclein contributed to the chromosome instability. hPTTG could be up-regulated by γ-synuclein, impling that hPTTG might participate in this chromosome instability progression related with γ-synuclein. hPTTG extensively effected on some important tumor-related genes, it increased expression of oncogene cyclin D1 and anti-apoptosis gene survivin, inhibited Gsk3β kinase activaty, and binded to p53.
人垂体瘤转化基因hPTTG，又称Securin，是有丝分裂中期纺锤体检验点通路的重要成员。它监控细胞周期的有序进行，保障细胞分裂的忠实性和遗传的稳定性，并且参与恶性转化和肿瘤发生。我们克隆表达了hPTTG基因，发现它影响细胞周期、促进细胞生长、引起恶性转化。我们使用RT-PCR和原位杂交方法，在食管癌中检测到hPTTG的高表达，统计学分析表明hPTTG的高表达与肿瘤的分化和转移密切相关。进一步深入研究hPTTG的调节机制，发现β-catenin／TCF通路上调hPTTG的转录和表达，并且食管癌标本的检测证明β-catenin的胞浆累积与hPTTG的高表达正相关；此外，MAPK通路抑制剂可抑制hPTTG的转录和表达；γ-synuclein引起染色体不稳定性并上调hPTTG的表达，hPTTG可能参与γ-synuclein引起不稳定性的过程。hPTTG广泛地影响一些重要的肿瘤相关基因，它上调癌基因cyclinD1和抗凋亡基因survivin的表达，抑制Gsk3β的激酶活性，并与p53结合。
综上所述，hPTTG的功能极其复杂，它参与细胞周期调控，沟通庞大的信号通路网络。探讨和阐明它参与肿瘤发生发展的作用机制，不仅对深入认识细胞周期和人类肿瘤大有裨益，还具有潜在的临床应用前景。
The malignant tumor is a complicated disease characterized with inordinate cell cycle, abnormal mitosis and genetic instability. In a certain sense, the malignant tumor is a kind of cell cycle diseases.
Human pituitary tumor transforming gene (hPTTG), also termed as Securin, is a key molecular of mitotic spindle checkpoint pathway. hPTTG surveilles orderly progression of cell cycle, ensures the fidelity of cell division and genetic stability, and participates in malignant transformation and tumorigenesis. We cloned and expressed hPTTG, observed its influences on cell cycle, and found that it accelerated cell proliferation and promoted cell malignant transformation. We detected its overexpression in human esophageal tumor tissues compared with the corresponding normal tissues, by using RT-PCR assay and in situ hybridization. On the other hand, the statistical analysis revealed that overexpression of hPTTG was closely associated with tumor differentiation and lymph node metastasis. We further investigated hPTTG's regulation mechanisms, demonstrated that β-catenin/TCF up-regulated hPTTG transcriptional avtivity and its expression. Subsequently, we detected the positive correlation between cytoplasmic accumulation of β-catenin and overexpression of hPTTG in 69 human esophageal tumors. Furthermore, the inhibitors of MAPK pathway could depress hPTTG's transcriptional activity and its expression, indicating that MAPK pathway may regulate hPTTG. We also found that γ-synuclein contributed to the chromosome instability. hPTTG could be up-regulated by γ-synuclein, impling that hPTTG might participate in this chromosome instability progression related with γ-synuclein. hPTTG extensively effected on some important tumor-related genes, it increased expression of oncogene cyclin D1 and anti-apoptosis gene survivin, inhibited Gsk3β kinase activaty, and binded to p53.
引文
1. Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1997,11: 433-41.
2. Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, Melmed S. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1999,13: 156-66.
3. Wang Z, Melmed S. Characterization of the murine pituitary tumor transforming gene (PTTG) and its promoter. Endocrinology 2000, 141: 763-71.
4. Prezant TR, Kadioglu P, Melmed S. An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for hPTTG family. J Clin Endocrinol Metab. 1999,84: 1149-52.
5. Chen L, Puri R, Lefkowitz EJ, Kakar SS. Identification of the human pituitary tumor transforming gene (hPTTG) family: molecular structure, expression, and chromosomal localization. Gene 2000, 248: 41-50.
6. Dominguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, Pintor-Toro JA. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG Oncogene 1998, 17: 2187-93.
7. Hosoe S. Search for the tumor-suppressor gene(s) on chromosome 5q, which may play an important role for the progression of lung cancer. Nippon Rinsho-Japanese Journal of Clinical Medicine 1996, 54: 482-6.
8. Hosoe S, Ueno K, Shigedo Y, Tachibana I, Osaki T, Kumagai T, Tanio Y, Kawase I, Nakamura Y & Kishimoto T. A frequent deletion of chromosome 5q21 in advanced small cell and non-small cell carcinoma of the lung. Cancer Res 1994, 54:1787-90.
9. Wu X, Hsu TC, Annegers JF, Amos CI, Fueger JJ & Spitz MR. A case-control study of nonrandom distribution of bleomycininduced chromatid breaks in lymphocytes of lung cancer cases. Cancer Res 1995, 55: 557-61.
10. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T & Saito H. Fusion of theplatelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 1997, 90: 4271-77.
11. Wlodarska I, Mecucci C, Baens M, Marynen P & van den Berghe H. ETV6 gene rearrangements in hematopoietic malignant disorders. Leukemia and Lymphoma 1996,2:287-95.
12. Kakar SS. Molecular cloning, genomic organization, and identification of the promoter for the human pituitary tumor transforming gene (PTTG). Gene 1999, 240:317-24.
13. Xin JH, Cowle A, Lachance P, Hassell JA. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is diferentially expressed in mouse embryonic cells. Genes Dev 1992, 6: 481-96.
14. Imagawa M, Chiu R, Karin M. Transcription factor AP-2 mediates induction by two diVerent signal-transduction pathways: protein kinase C and cAMP. Cell 1987, 51: 251-60.
15. Faisst S, Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res 1992,20:3-26.
16. Clem AL, Hamid T, Kakar SS. Characterization of the role of Sp1 and NF-Y in differential regulation of PTTG/securin expression in tumor cells. Gene 2003, 322: 113-21.
17. Wang Z, Melmed S. Pituitary tumor transforming gene (PTTG) transforming and transactivation activity. J Biol Chem 2000, 275: 7459-61.
18. Saez C, Japon MA, Ramos-Morales F, Romero F, Segura DI, Tortolero M, Pintor-Toro JA. hpttg is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 1999,18: 5473-6.
19. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas.J Clin Endocrinol Metab 1999, 84: 761-7.
20. Hunter JA, Skelly RH, Aylwin SJ, Geddes JF, Evanson J, Besser GM, Monson JP, Burrin JM. The relationship between pituitary tumour transforming gene (PTTG) expression and in vitro hormone and vascular endothelial growth factor (VEGF)secretion from human pituitary adenomas. Eur J Endocrinol 2003, 148:203-11.
21. McCabe CJ, Khaira JS, Boelaert K, Heaney AP, Tannahill LA, Hussain S, Mitchell R, Olliff J, Sheppard MC, Franklyn JA, Gittoes NJ. Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. Clin Endocrinol 2003, 58: 141-50.
22. Shibata Y, Haruki N, Kuwabara Y, Nishiwaki T, Kato J, Shinoda N, Sato A, Kimura M, Koyama H, Toyama T, Ishiguro H, Kudo J, Terashita Y, Konishi S, Fujii Y. Expression of PTTG (pituitary tumor transforming gene) in esophageal cancer. Jpn J Clin Oncol 2002, 32:233-7.
23. Wen CY, Nakayama T, Wang AP, Nakashima M, Ding YT, Ito M, Ishibashi H, Matsuu M, Shichijo K, Sekine I. Expression of pituitary tumor transforming gene in human gastric carcinoma. World J Gastroenterol 2004,10: 481-3.
24. Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S. Expression of pituitary-tumour transforming gene in colorectal tumours. The Lancet 2000, 355: 716-9.
25. Puri R, Tousson A, Chen L, Kakar SS. Molecular cloning of pituitary tumor transforming gene 1 from ovarian tumors and its expression in tumors. Cancer Lett 2001, 163: 131-9.
26. Solbach C, Roller M, Fellbaum C, Nicoletti M, Kaufmann M. PTTG mRNA expression in primary breast cancer: a prognostic marker for lymph node invasion and tumor recurrence. Breast 2004, 13: 80-1.
27. Kalar SS, Jennes L. Molecular cloning and characterization of the tumor transforming gene (TUTR1): a novel gene in human tumorigenesis. Cytogenet Cell Genet 1998, 84:211-6.
28. Honda S, Hayashi M, Kobayashi Y, Ishikawa Y, Nakagawa K, Tsuchiya E. A role for the pituitary tumor-transforming gene in the genesis and progression of non-small cell lung carcinomas. Anticancer Res 2003, 23: 3775-82.
29. Boelaert K, McCabe CJ, Tannahill LA, Gittoes NJ, Holder RL, Watkinson JC, Bradwell AR, Sheppard MC, Franklyn JA. Pituitary tumor transforming gene and fibroblastgrowth factor-2 expression: potential prognostic indicators in differentiated thyroid cancer. J Clin Endocrinol Metab 2003, 88: 2341-7.
30. Amon A. The spindle checkpoint Curr Opin Genet Dev 1999, 9: 69-75.
31. Burke DJ. Complexity in the spindle checkpoint. Curr Opin Genet Dev 2000, 10: 26-31.
32. Gardner RD, Burke DJ. The spindle checkpoint: two transitions, two pathways. Trends in cell Biology 2000,10: 154-8.
33. Zhou J, Yao J, Joshi HC. Attachment and tension in the spindle assembly checkpoint. J Cell Sci 2002, 115:3547-55.
34. Gillett ES, Sorger PK. Tracing the pathway of spindle assembly checkpoint signaling. Dev Cell 2001, 1: 162-4.
35. Hoyt MA. A new view of the spindle checkpoint. J Cell Biol 2001, 154: 909-11.
36. Li R and Murray AW. Feedback control of mitosis in budding yeast. Cell 1991, 66: 519-31.
37. Hoyt MA, Totis L and Roberts BT. S. cerevisiae genes requiredfor cell cycle arrest in response to loss of microtubule function. Cell 1991, 66: 507-17.
38. Weiss E and Winey M. The S cerevisiae SPB duplication gene MPS1 is part of a mitotic checkpoint. J Cell Biol 1996, 132: 111-23.
39. Li Y and Benezra R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 1996, 274: 246-8.
40. Jin DY, Spencer F and Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 1998, 93: 81-91.
41. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature 1998, 392: 300-3.
42. Taylor SS, Ha E and McKeon F. The human homologue of Bub3 is required for kinetochore localization and a Mad3/Bubl-related protein kinase. J Cell Biol 1998, 142: 1-11.
43. Chan GK, Schaar BT and Yen TJ. Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F andhBUBR1. J Cell Biol 1998, 143: 49-63.
44. Chan GK, Jablonski SA, Sudakin V, Hittle JC and Yen TJ. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol 1999, 146:941-54.
45. Fang G, Yu H and Kirschner MW. Control of mitotic transitions by the anaphase-promoting complex. Philos Trans R Soc Lond B Biol Sci 1999, 354: 1583-90.
46. Zachariae W and Nasmyth K. Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 1999, 13: 2039-58.
47. Visintin R, Prinz S and Amon A. CDC20 and CDH1: A family of substrate-specific activators of APC-dependent proteolysis. Science 1997, 278: 460-63.
48. Hwang LH, Lau LF, Smith DL, Mistrot CA, Hardwick KG, Hwang ES, Amon A and Murray AW. Budding yeast Cdc20: a target of the spindle checkpoint. Science 1998, 279: 1041-44.
49. Shirayama M, Zachariae W, Ciosk R and Nasmyth K. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J 1998, 17: 1336-49.
50. Fang G, Yu H and Kirschner MW. Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol Cell 1998, 2: 163-71.
51. Yamamoto A, Guacci V and Koshland D. Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J Cell Biol 1996, 133:99-110.
52. Cohen-Fix O, Peters JM, Kirschner MW and Koshland D. Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC dependent degradation of the anaphase inhibitor Pdslp. Genes Dev 1996, 10: 3081-93.
53. Funabiki H, Yamano H, Kumada K, Nagao K, Hunt T and Yangida M. Cut2 proteolysis required for sister-chromatid separation in fission yeast. Nature 1996, 381: 438-41.
54. Zou H, McGarry TJ, Bernal T and Kirschner MW. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 1999,285: 418-22.
55. Thornton BR, Toczyski DP. Securin and B-cyclin/CDK are the essential targets of the APC. Nat cell Biol 2003, 5: 1090-4.
56. Herbert M, Levasseur M, Homer H, Yallop K, Murdoch A, McDougall A. Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nat Cell Biol 2003, 5: 1023-5.
57. Salah SM, Nasmyth K. Destruction of the securin Pds1p occurs at the onset of anaphase during both meiotic divisions in yeast. Chromosoma 2000, 109: 27-34.
58. Zur A, Brandeis M. Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis. EMBO J 2001, 20: 792-801.
59. Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J Cell Biol 2002, 157: 1125-37.
60. Leismann O, Lehner CF. Drosophila securin destruction involves a D-box and a KEN-box and promotes anaphase in parallel with Cyclin A degradation. J Cell Sci 2003,116:2453-60.
61. Yanagida M. Cell cycle mechanisms of sister chromatid separation; roles of Cut1/separin and Cut2/securin. Genes Cells 2000, 5: 1-8.
62. Agarwal R, Cohen-Fix O. Phosphorylation of the mitotic regulator Pds1/securin by Cdc28 is required for efficient nuclear localization of Esp1/separase. Genes Dev 2002, 16: 1371-82.
63. Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M and Nasmyth K. An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 1998, 93: 1067-76.
64. Uhlmann F, Lottspeich F and Nasmyth K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 1999, 400: 37-42.
65. Uhlmann F, Wernek W, Poupart MA, Koonin E and Nasmyth K. Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 2000, 103: 375-86.
66. Hauf S, Waizenegger IC and Peters JM. Cohesion cleavage by separase required for anaphase and cytokinesis in human cells. Science 2001, 293: 1320-23.
67. Li Y, Gorbea C, Mahaffey D, Rechsteiner M and Benezra R. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci USA 1997, 94: 12431-6.
68. Fang G, Yu H and Kirschner MW. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 1998, 12: 1871-83.
69. Kim SH, Lin DP, Matsumoto S, Kitazono A and Matsumoto T. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint. Science 1998, 279: 1045-7.
70. Sudakin V, Chan GK T and Yen TJ. Checkpoint inhibition the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, MAD2. J Cell Biol 2001, 154: 925-36.
71. Tang Z, Bharadwaj R, Li B and Yu H. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell 2001, 1: 227-37.
72. Fang G. Checkpoint protein BubRl acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol Biol Cell 2002, 13: 755-66.
73. Ramos-Morales F, Dominguez A, Romero F, Luna R, Multon MC, Pintor-Toro J and Tortolero M. Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene product. Oncogene 2000, 19: 403-9.
74. Yu R, Ren SG, Horwitz GA, Wang Z, Melmed S. Pituitary tumor transforming gene (PTTG) regulates placental JEG-3 cell division and survival: evidence from live cell imaging. Mol Endocrinol 2000, 14: 1137-46.
75. Jallepalli PV, Waizenegger IC, Bunz F, Langer S, Speicher MR, Peters JM, Kinzler K W, Vogelstein B, Lengauer C. Securin is required for chromosomal stability in human cells. Cell 2001,105: 445-57.
76. Wang Z, Yu R, Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol Endocrinol 2001, 15: 1870-9.
77. Mei J, Huang X, Zhang P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. Curr Biol 2001,11:1197-201.
78. Wang Z, Moro E, Kovacs K, Yu R, Melmed S. Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes. Proc Natl Acad Sci U S A 2003, 100: 3428-32.
79. Yu R, Lu W, Chen J, McCabe CJ, Melmed S. Overexpressed pituitary tumor-transforming gene causes aneuploidy in live human cells. Endocrinology 2003, 144: 4991-8.
80. Christopoulou L, Moore JD, Tyler-Smith C. Over-expression of wild-type Securin leads to aneuploidy in human cells. Cancer Lett 2003, 202: 213-8.
81. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 1999, 5: 1317-21.
82. Boelaert K, Tannahill LA, Bulmer JN, Kachilele S, Chan SY, Kim D, Gittoes NJ, Franklyn JA, Kilby MD, McCabe CJ. A potential role for PTTG/securin in the developing human fetal brain. FASEB J 2003, 17: 1631-9.
83. Chien W, Pei L. A novel binding factor facilitates nuclear translocation and transcriptional activation function of the pituitary tumor-transforming gene product. J Biol Chem 2000, 275: 19422-7.
84. McCabe CJ, Boelaert K, Tannahill LA, Heaney AP, Stratford AL, Khaira JS, Hussain S, Sheppard MC, Franklyn JA, Gittoes NJ. Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. J Clin Endocrinol Metab 2002, 87: 4238-44.
85. Ishikawa H, Heaney AP, Yu R, Horwitz GA, Melmed S. Human pituitary tumor-transforming gene induces angiogenesis. J Clin Endocrinol Metab 2000, 86: 867-74.
86. Theodosiou A, Ashworth A. MAP kinase phosphatases. Genome Biol 2002, 3: REVIEWS3009.
87. Hazzalin CA, Mahadevan LC. MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 2002, 3: 30-40.
88. Yang SH, Sharrocks AD, Whitmarsh AJ. Transcriptional regulation by the MAPkinase signaling cascades. Gene 2003, 320: 3-21.
89. Gerthoffer WT, Singer CA. MAPK regulation of gene expression in airway smooth muscle. Respir Physiol Neurobiol 2003, 137: 237-50.
90. Rincon M. MAP-kinase signaling pathways in T cells. Curr Opin Immunol 2001, 13: 339-45.
91. Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol 1999, 71:479-500.
92. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001, 22: 153-83.
93. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001, 410: 37-40.
94. Peter AT, Dhanasekaran N. Apoptosis of granulosa cells: a review on the role of MAPK-signalling modules. Reprod Domest Anim 2003, 38: 209-13.
95. Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J 2000, 14: 2147-57.
96. Pei L. Activation of mitogen-activated protein kinase cascade regulates pituitary tumor-transforming gene transactivation function. J Biol Chem 2000, 275: 31191-8.
97. Pei L. Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J Biol Chem 2001, 276: 8484-91.
98. Bernal JA, Luna R, Espina A, Lazaro I, Ramos-Morales F, Romero F, Arias C, Silva A, Tortolero M, Pintor-Toro JA. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet 2002, 32: 306-11.
99. Zhou Y, Mehta KR, Choi AP, Scolavino S, Zhang X. DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 2003, 278: 462-70.
100. Romero F, Multon MC, Ramos-Morales F, Dominguez A, Bernal JA, Pintor-Toro JA, Tortolero M. Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase. Nucleic Acids Res 2001, 29: 1300-7.
101. Smith GC, Jackson SP. The DNA-dependent protein kinase. Genes Dev 1999, 13: 916-34.
102. Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 1998, 17: 3309-18.
103. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 2000, 14: 2807-12.
104. d'Adda di Fagagna F, Hande MP, Tong WM, Roth D, Lansdorp PM, Wang ZQ, Jackson SP. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol 2001, 11: 1192-6.
105. Lee IA, Seong C, Choe IS. Cloning and expression of human cDNA encoding human homologue of pituitary tumor transforming gene. Biochem Mol Biol Int 1999, 47: 891-897.
106. Morgan DO. Principles of CDK regulation. Nature 1995, 374: 131.
107. Sherr CJ, Kato J, Quelle DE, Matsuoka M, Roussel MF. D-type cyclins and their cyclin-dependent kinases: G1 phase integrators of the mitogenic response. Cold Spring Harb Symp Quant Biol 1994, 59: 11-9.
108. Terada Y, Tatsuka M, Jinno S, Okayama H. Requirement for tyrosine phosphorylation of Cdk4 in Gl arrest induced by ultraviolet irradiation. Nature 1995,376:358-62.
109. Makela TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA. A cyclin associated with the CDK-activating kinase MO15. Nature 1994, 371: 254-7.
110. Morgan DO, Fisher RP, Espinoza FH, Farrell A, Nourse J, Chamberlin H, Jin P. Control of eukaryotic cell cycle progression by phosphorylation of cyclin-dependent kinases. Cancer J Sci Am 1998, 4 Suppl 1: S77-83.
111. Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996, 382: 511-7.
112. Harper JW. Cyclin dependent kinase inhibitors. Cancer Surv 1997, 29: 91-107.
113. Aprelikova O, Xiong Y, Liu ET. Both pl6 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK- activating kinase. J Biol Chem 1995, 270: 18195-7.
114. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D,Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell 1993, 75: 817-25.
115. Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kipl is abrogated by c-Myc. Embo J 1996, 15: 6595-604.
116. Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991, 65: 701-13.
117. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of Gl cyclin-dependent kinases. Cell 1993, 75: 805-16.
118. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997, 1:3-11.
119. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science 1996, 271:1744-7.
120. Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA, Fukasawa K. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclinE overexpression. Oncogene 2000, 19: 1635-46.
121. Lavedan C. The synuclein family. Genome Res 1998, 8: 871-80.
122. George JM. The synucleins. Genome Biology 2001, 3: reviews3002.1 - reviews3002.6
123. Mukaetova-Ladinska EB, Hurt J, Jakes R, Xuereb J, Honer WG, Wischik CM. Alpha-synuclein inclusions in Alzheimer and Lewy body diseases. J Neuropathol Exp Neurol 2000, 5: 408-17.
124. Li JY, Henning Jensen P, Dahlstrom A. Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience 2002, 2: 463-78.
125. Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 1997, 4: 759-64.
126. Ninkina NN, Alimova-Kost MV, Paterson JW, Delaney L, Cohen BB, Imreh S, Gnuchev NV, Davies AM, Buchman VL. Organization, expression and polymorphism??of the human persyn gene. Hum Mol Genet 1998, 7: 1417-24.
127. Jia T, Liu YE, Liu J, Shi YE. Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res 1999, 3: 742-7.
128. Bruening W, Giasson BI, Klein-Szanto AJ, Lee VM, Trojanowski JQ, Godwin AK. Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer 2000, 9: 2154-63.
129. Wu K, Weng Z, Tao Q, Lin G, Wu X, Qian H, Zhang Y, Ding X, Jiang Y, Shi YE. Stage-specific expression of breast cancer-specific gene gamma-synuclein. Cancer Epidemiol Biomarkers Prev 2003, 12: 920-5.
130. Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J. Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 2003, 63: 664-73.
131. Jiang Y, Liu YE, Lu A, Gupta A, Goldberg ID, Liu J, Shi YE. Stimulation of estrogen receptor signaling by gamma synuclein. Cancer Res 2003, 63: 3899-903.
132. Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK. Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J Biol Chem 2002, 277: 35050-60.
133. Surguchov A, Palazzo RE, Surgucheva I. Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. Cell Motil Cytoskeleton 2001, 49: 218-28.
134. Adams RR, Carmene M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends cell boil 2001, 11: 49-54.
135. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic ans amplified in human colotectal cancer. EMBO J 1998, 17: 3052-65.
136. Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S, Otsu M. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 1998, 17: 667-676.
137. Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT.Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity isstimulated by survivin binding and phosphorylation. Mol Biol Cell 2002, 13: 3064-77.
138. Pereira G, Schiebel E. Separase regulates INCENP-Aurora B anaphase spindle function through Cdcl4. Science 2003, 302: 2120-24.
139. Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP, and Survivin in motosis. Mol Biol Cell 2003, 14: 3325-41.
140. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997, 3:917-21.
141. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998, 396: 580-4.
142. Bosher JM, Labouesse M. RNA interference: genetic wand and genetic watchdog. Nat Cell Biol 2000, 2: E31-6.
143. Harmon GJ. RNA interference. Nature 2002, 418: 244-51.
144. Cullen BR. RNA interference: antiviral defense and genetic tool. Nat Immunol 2002,3:597-9.
145. Agami R.RNAi and related mechanisms and their potential use for therapy. Curr Opin Chem Biol 2002, 6: 829-34.
146. Dudley NR, Goldstein B. RNA interference: silencing in the cytoplasm and nucleus. Curr Opin Mol Ther 2003, 5:113-7.
147. Cottrell TR, Doering TL. Silence of the strands: RNA interference in eukaryotic pathogens. Trends Microbiol 2003, 11: 37-43.
148. Kawasaki H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi mediated gene silencing in the cytoplasm of human cells. Nucleic Acids Res 2003, 31: 700-7.
149. Caplen NJ, Fleenor J, Fire A, Morgan RA. dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference. Gene 2000, 252: 95-105.
150. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998,391:806-11.
151. Enders GH. Cyclins in breast cancer: too much of a good thing. Breast Cancer Res 2002,4: 145-7.
152. Motokura T, Arnold A. Cyclin D and oncogenesis. Curr Opin Genet Dev 1993, 3: 5-10.
153. Arnold A. The cyclin D1/PRAD1 oncogene in human neoplasia. J Investig Med 1995,43:543-9.
154. Nichols GE, Williams ME, Gaffey MJ, Stoler MH. Cyclin D1 gene expression in human cervical neoplasia. Mod Pathol 1996, 9: 418-25.
155. Donnellan R, Chetty R. Cyclin D1 and human neoplasia. Mol Pathol 1998, 51:1-7.
156. Osman I, Scher H, Zhang ZF, Soos TJ, Hamza R, Eissa S, Khaled H, Koff A, Cordon-Cardo C. Expression of cyclin D1, but not cyclins E and A, is related to progression in bilharzial bladder cancer. Clin Cancer Res 1997, 3: 2247-51.
157. Arber N, Hibshoosh H, Moss SF, Sutter T, Zhang Y, Begg M, Wang S, Weinstein IB, Holt PR. Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. Gastroenterology 1996, 110: 669-74.
158. Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, El-Naggar A, Hong WK, Hittelman WN. Dysregulated cyclin Dl expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification. Oncogene 1998, 17: 2313-22.
159. Weinstein IB. Relevance of cyclin Dl and other molecular markers to cancer chemoprevention. J Cell Biochem Suppl 1996, 25: 23-8.
160. Dutta A, Chandra R, Leiter LM, Lester S. Cyclins as markers of tumor proliferation: immunocytochemical studies in breast cancer. Proc Natl Acad Sci U S A 1995,92:5386-90.
161. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin Dl ablation. Nature 2001, 411: 1017-21.
162. Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 2001,40: 1117-23.
163. Giodini A, Kallio MJ, Wall NR, Gorbsky GJ, Tognin S, Marchisio PC, Symons M,Altieri DC. Regulation of microtubule stability and mitotic progression by survivin. Cancer Res 2002, 62: 2462-7.
164. Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi F, Santambrogio L, Coggi G, Bosari S. Survivin gene expression in early-stage non-small cell lung cancer. J Pathol 2003, 200: 620-6.
165. Lu CD, Altieri DC, Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 1998, 58: 1808-12.
166. Miyachi K, Sasaki K, Onodera S, Taguchi T, Nagamachi M, Kaneko H, Sunagawa M. Correlation between survivin mRNA expression and lymph node metastasis in gastric cancer. Gastric Cancer 2003, 6: 217-24.
167. Tu SP, Jiang XH, Lin MC, Cui JT, Yang Y, Lum CT, Zou B, Zhu YB, Jiang SH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC. Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 2003, 6: 7724-32.
168. Tanaka K, Iwamoto S, Gon G, Nohara T. Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 2000, 6: 127-34.
169. Kennedy SM, O'Driscoll L, Purcell R, Fitz-Simons N, McDermott EW, Hill AD, O'Higgins NJ, Parkinson M, Linehan R, Clynes M. Prognostic importance of survivin in breast cancer. BrJ Cancer 2003, 88: 1077-83.
170. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 1998,58:5071-4.
171. Kawasaki H, Toyoda M, Shinohara H, Okuda J, Watanabe I, Yamamoto T, Tanaka K, Tenjo T, Tanigawa N. Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer 2001, 91: 2026-32.
172. Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, Nakano T, Suzuki A. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000, 31: 1080-5.
173. Ikeguchi M, Ueda T, Sakatani T, Hirooka Y, Kaibara N. Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma. Diagn Mol Pathol 2002, 11: 33-40.
174. Kato J, Kuwabara Y, Mitani M, Shinoda N, Sato A, Toyama T, Mitsui A, Nishiwaki T, Moriyama S, Kudo J, Fujii Y Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer 2001, 95: 92-5.
175. Swana HS, Grossman D, Anthony JN, Weiss RM, Altieri DC.Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. N Engl J Med 1999,341:452-3.
176. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 2001, 92: 271-8.
177. Yoshida H, Ishiko O, Sumi T, Matsumoto Y, Ogita S. Survivin, bcl-2 and matrix metalloproteinase-2 enhance progression of clear cell- and serous-type ovarian carcinomas. Int J Oncol 2001, 19: 537-42.
178. Grossman D, McNiff JM, Li F, Altieri DC.Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999, 113: 1076-81.
179. Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC. Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. The Lancet 1998, 351: 882-3.
180. Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000, 19: 617-23.
181. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J, Dombret H, Reyes F, Diebold J, Gisselbrecht C, Salles G, Altieri DC, Molina TJ. Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 2000, 96: 1921-5.
182. Adida C, Recher C, Raffoux E, Daniel MT, Taksin AL, Rousselot P, Sigaux F, Degos L, Altieri DC, Dombret H. Expression and prognostic significance of survivin in denovo acute myeloid leukaemia. Br J Haematol 2000, 111: 196-203.
183. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 2000, 60: 6788-93.
184. Ryan KM, Phillips AC, Vousden KH. Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 2001, 13: 332-7.
185. Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol 2002, 14:86-91.
186. Albrechtsen N, Dornreiter I, Grosse F, Kim E, Wiesmuller L, Deppert W. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 1999, 18: 7706-17.
187. Miller JR. The Wnts. Genome Biol 2002, 3: REVIEWS3001.
188. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev 1997,11:3286-305.
189. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 2000, 287: 1606-9.
190. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000, 103: 311-20.
191. Polakis P. Wnt signaling and cancer. Genes Dev 2000, 14: 1837-51.
192. van Es JH, Barker N, Clevers H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 2003, 13: 28-33.
193. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science 1998,281: 1509-12.
194. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature1999, 398: 422-6.
195. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. The cyclin Dl gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 1999,96: 5522-7.
196. Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM. The metalloproteinase matrilysin is a target of beta-catenintransactivation in intestinal tumors. Oncogene 1999, 18: 2883-91.
197. Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T, Clevers H. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 1999,285: 1923-6.
198. He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999, 99: 335-45.
199. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 2000, 14: 585-95.
200. Koh TJ, Bulitta CJ, Fleming JV, Dockray GJ. Varro A, Wang TC. Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest 2000, 106: 533-9.
201. Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S. Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Cancer Res 2000, 60: 4761-6.
202. Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C, Garcia PD, Randazzo FM, et al. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors. Proc Natl Acad Sci U S A 2001, 98. 14973-8.
203. Zhang T, Otevrel T, Gao Z, Ehrlich SM, Fields JZ, Boman BM. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 2001, 61: 8664-7.
204. Rockman SP, Currie SA, Ciavarella M, Vincan E, Dow C, Thomas RJ, Phillips WA. Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J Biol Chem 2001, 276: 45113-9.
205. Kolligs FT, Nieman MT, Winer I, Hu G, Van Mater D, Feng Y, Smith IM, Wu R, Zhai Y, Cho KR, Fearon ER. ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell 2002, 1: 145-55.
206. Shimokawa T, Furukawa Y, Sakai M, Li M, Miwa N, Lin Y M, Nakamura Y. Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex. Cancer Res 2003, 63: 6116-20.
207. Nakamura Y. Cleaning up on beta-catenin. Nat Med 1997, 3: 499-500.
208. Gumbiner BM. Signal transduction of beta-catenin. Curr Opin Cell Biol 1995, 7: 634-40.
209. Alexander N, Wong CS, Pignatelli M. β-catenin--A linchpin in colorectal carcinogenesis. Am J Pathol 2002,160: 389-401.
210. Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci. 1999, 56: 523-37.
211. Akiyama T. Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 2000, 11: 273-82.
212. van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 1997, 88: 789-99.
213. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996,382:638-42.
214. Brantjes H, Barker N, van Es J, Clevers H.TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 2002, 383: 255-61.
215. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995, 378: 785-9.
216. Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinosi-tol 3-Kinase/Akt cell survival pathway. J Biol Chem 1998, 273: 19929-32.
217. Bijur GN, De Sarno P, Jope RS. Glycogen synthase kinase-3β facilitates staurospor-ine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 2000, 275: 7583-90.
218. Nikolakaki E, Coffer PJ, Hemelsoet R, Woodgett JR, Defize LH. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their trans-aetivating potential in intact cells. Oncogene 1993, 8: 833-40.
219. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000, 14: 2501-14.
220. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3β regulates eyelin D1 proteolysis and subcellular localization. Genes Dev 1998, 12: 3499-511.
221. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 2003, 22: 395-403.
222. Shapiro P. Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy. Crit Rev Clin Lab Sci 2002, 39: 285-330.
223. Santen RJ, Song RX, McPherson R, Kumar R, Adam L, Jeng MH, Yue W. The role of mitogen-activated protein(MAP) kinase in breast cancer, J Steroid Biochem Mol Biol 2002, 80: 239-56.
224. Li LD, Lu FZ, Zhang SW, Mu R, Sun XD, Huan-Pu XM, Sun J, Zhou YS, Ou-Yang NH, Rao KQ, Chen YD, Sun AM, Xue ZF, Xia Y. The death epidemiology analysis of malignancy in china in 1990-1992. Chinese J oncol 1996, 18: 403-7.
225. Parkin M. Global cancer statistics in the year 2000. The Lancet 2001, 2: 533-43.
226. Kimura Y, Shiozaki H, Doki Y, Yamamoto M, Utsunomiya T, Kawanishi K, Fukuchi N, Inoue M, Tsujinaka T, Monden M. Cytoplasmic beta-catenin in esophageal cancers. Int J Cancer 1999, 84: 174-8.
227. Ninomiya I, Endo Y, Fushida S, Sasagawa T, Miyashita T, Fujimura T, Nishimura G, Tani T, Hashimoto T, Yagi M, Shimizu K, Ohta T, et al. Alteration of beta-catenin expression in esophageal squamous-cell carcinoma. Int J Cancer 2000, 85: 757-61.
228．周晓波，吕宁，张维等Beta-连环蛋白在食管癌组织中的表达及意义。癌症2002，21：877-80．
2. Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, Melmed S. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1999,13: 156-66.
3. Wang Z, Melmed S. Characterization of the murine pituitary tumor transforming gene (PTTG) and its promoter. Endocrinology 2000, 141: 763-71.
4. Prezant TR, Kadioglu P, Melmed S. An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for hPTTG family. J Clin Endocrinol Metab. 1999,84: 1149-52.
5. Chen L, Puri R, Lefkowitz EJ, Kakar SS. Identification of the human pituitary tumor transforming gene (hPTTG) family: molecular structure, expression, and chromosomal localization. Gene 2000, 248: 41-50.
6. Dominguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, Pintor-Toro JA. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG Oncogene 1998, 17: 2187-93.
7. Hosoe S. Search for the tumor-suppressor gene(s) on chromosome 5q, which may play an important role for the progression of lung cancer. Nippon Rinsho-Japanese Journal of Clinical Medicine 1996, 54: 482-6.
8. Hosoe S, Ueno K, Shigedo Y, Tachibana I, Osaki T, Kumagai T, Tanio Y, Kawase I, Nakamura Y & Kishimoto T. A frequent deletion of chromosome 5q21 in advanced small cell and non-small cell carcinoma of the lung. Cancer Res 1994, 54:1787-90.
9. Wu X, Hsu TC, Annegers JF, Amos CI, Fueger JJ & Spitz MR. A case-control study of nonrandom distribution of bleomycininduced chromatid breaks in lymphocytes of lung cancer cases. Cancer Res 1995, 55: 557-61.
10. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T & Saito H. Fusion of theplatelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 1997, 90: 4271-77.
11. Wlodarska I, Mecucci C, Baens M, Marynen P & van den Berghe H. ETV6 gene rearrangements in hematopoietic malignant disorders. Leukemia and Lymphoma 1996,2:287-95.
12. Kakar SS. Molecular cloning, genomic organization, and identification of the promoter for the human pituitary tumor transforming gene (PTTG). Gene 1999, 240:317-24.
13. Xin JH, Cowle A, Lachance P, Hassell JA. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is diferentially expressed in mouse embryonic cells. Genes Dev 1992, 6: 481-96.
14. Imagawa M, Chiu R, Karin M. Transcription factor AP-2 mediates induction by two diVerent signal-transduction pathways: protein kinase C and cAMP. Cell 1987, 51: 251-60.
15. Faisst S, Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res 1992,20:3-26.
16. Clem AL, Hamid T, Kakar SS. Characterization of the role of Sp1 and NF-Y in differential regulation of PTTG/securin expression in tumor cells. Gene 2003, 322: 113-21.
17. Wang Z, Melmed S. Pituitary tumor transforming gene (PTTG) transforming and transactivation activity. J Biol Chem 2000, 275: 7459-61.
18. Saez C, Japon MA, Ramos-Morales F, Romero F, Segura DI, Tortolero M, Pintor-Toro JA. hpttg is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 1999,18: 5473-6.
19. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas.J Clin Endocrinol Metab 1999, 84: 761-7.
20. Hunter JA, Skelly RH, Aylwin SJ, Geddes JF, Evanson J, Besser GM, Monson JP, Burrin JM. The relationship between pituitary tumour transforming gene (PTTG) expression and in vitro hormone and vascular endothelial growth factor (VEGF)secretion from human pituitary adenomas. Eur J Endocrinol 2003, 148:203-11.
21. McCabe CJ, Khaira JS, Boelaert K, Heaney AP, Tannahill LA, Hussain S, Mitchell R, Olliff J, Sheppard MC, Franklyn JA, Gittoes NJ. Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. Clin Endocrinol 2003, 58: 141-50.
22. Shibata Y, Haruki N, Kuwabara Y, Nishiwaki T, Kato J, Shinoda N, Sato A, Kimura M, Koyama H, Toyama T, Ishiguro H, Kudo J, Terashita Y, Konishi S, Fujii Y. Expression of PTTG (pituitary tumor transforming gene) in esophageal cancer. Jpn J Clin Oncol 2002, 32:233-7.
23. Wen CY, Nakayama T, Wang AP, Nakashima M, Ding YT, Ito M, Ishibashi H, Matsuu M, Shichijo K, Sekine I. Expression of pituitary tumor transforming gene in human gastric carcinoma. World J Gastroenterol 2004,10: 481-3.
24. Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S. Expression of pituitary-tumour transforming gene in colorectal tumours. The Lancet 2000, 355: 716-9.
25. Puri R, Tousson A, Chen L, Kakar SS. Molecular cloning of pituitary tumor transforming gene 1 from ovarian tumors and its expression in tumors. Cancer Lett 2001, 163: 131-9.
26. Solbach C, Roller M, Fellbaum C, Nicoletti M, Kaufmann M. PTTG mRNA expression in primary breast cancer: a prognostic marker for lymph node invasion and tumor recurrence. Breast 2004, 13: 80-1.
27. Kalar SS, Jennes L. Molecular cloning and characterization of the tumor transforming gene (TUTR1): a novel gene in human tumorigenesis. Cytogenet Cell Genet 1998, 84:211-6.
28. Honda S, Hayashi M, Kobayashi Y, Ishikawa Y, Nakagawa K, Tsuchiya E. A role for the pituitary tumor-transforming gene in the genesis and progression of non-small cell lung carcinomas. Anticancer Res 2003, 23: 3775-82.
29. Boelaert K, McCabe CJ, Tannahill LA, Gittoes NJ, Holder RL, Watkinson JC, Bradwell AR, Sheppard MC, Franklyn JA. Pituitary tumor transforming gene and fibroblastgrowth factor-2 expression: potential prognostic indicators in differentiated thyroid cancer. J Clin Endocrinol Metab 2003, 88: 2341-7.
30. Amon A. The spindle checkpoint Curr Opin Genet Dev 1999, 9: 69-75.
31. Burke DJ. Complexity in the spindle checkpoint. Curr Opin Genet Dev 2000, 10: 26-31.
32. Gardner RD, Burke DJ. The spindle checkpoint: two transitions, two pathways. Trends in cell Biology 2000,10: 154-8.
33. Zhou J, Yao J, Joshi HC. Attachment and tension in the spindle assembly checkpoint. J Cell Sci 2002, 115:3547-55.
34. Gillett ES, Sorger PK. Tracing the pathway of spindle assembly checkpoint signaling. Dev Cell 2001, 1: 162-4.
35. Hoyt MA. A new view of the spindle checkpoint. J Cell Biol 2001, 154: 909-11.
36. Li R and Murray AW. Feedback control of mitosis in budding yeast. Cell 1991, 66: 519-31.
37. Hoyt MA, Totis L and Roberts BT. S. cerevisiae genes requiredfor cell cycle arrest in response to loss of microtubule function. Cell 1991, 66: 507-17.
38. Weiss E and Winey M. The S cerevisiae SPB duplication gene MPS1 is part of a mitotic checkpoint. J Cell Biol 1996, 132: 111-23.
39. Li Y and Benezra R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 1996, 274: 246-8.
40. Jin DY, Spencer F and Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 1998, 93: 81-91.
41. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature 1998, 392: 300-3.
42. Taylor SS, Ha E and McKeon F. The human homologue of Bub3 is required for kinetochore localization and a Mad3/Bubl-related protein kinase. J Cell Biol 1998, 142: 1-11.
43. Chan GK, Schaar BT and Yen TJ. Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F andhBUBR1. J Cell Biol 1998, 143: 49-63.
44. Chan GK, Jablonski SA, Sudakin V, Hittle JC and Yen TJ. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol 1999, 146:941-54.
45. Fang G, Yu H and Kirschner MW. Control of mitotic transitions by the anaphase-promoting complex. Philos Trans R Soc Lond B Biol Sci 1999, 354: 1583-90.
46. Zachariae W and Nasmyth K. Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 1999, 13: 2039-58.
47. Visintin R, Prinz S and Amon A. CDC20 and CDH1: A family of substrate-specific activators of APC-dependent proteolysis. Science 1997, 278: 460-63.
48. Hwang LH, Lau LF, Smith DL, Mistrot CA, Hardwick KG, Hwang ES, Amon A and Murray AW. Budding yeast Cdc20: a target of the spindle checkpoint. Science 1998, 279: 1041-44.
49. Shirayama M, Zachariae W, Ciosk R and Nasmyth K. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J 1998, 17: 1336-49.
50. Fang G, Yu H and Kirschner MW. Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol Cell 1998, 2: 163-71.
51. Yamamoto A, Guacci V and Koshland D. Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J Cell Biol 1996, 133:99-110.
52. Cohen-Fix O, Peters JM, Kirschner MW and Koshland D. Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC dependent degradation of the anaphase inhibitor Pdslp. Genes Dev 1996, 10: 3081-93.
53. Funabiki H, Yamano H, Kumada K, Nagao K, Hunt T and Yangida M. Cut2 proteolysis required for sister-chromatid separation in fission yeast. Nature 1996, 381: 438-41.
54. Zou H, McGarry TJ, Bernal T and Kirschner MW. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 1999,285: 418-22.
55. Thornton BR, Toczyski DP. Securin and B-cyclin/CDK are the essential targets of the APC. Nat cell Biol 2003, 5: 1090-4.
56. Herbert M, Levasseur M, Homer H, Yallop K, Murdoch A, McDougall A. Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nat Cell Biol 2003, 5: 1023-5.
57. Salah SM, Nasmyth K. Destruction of the securin Pds1p occurs at the onset of anaphase during both meiotic divisions in yeast. Chromosoma 2000, 109: 27-34.
58. Zur A, Brandeis M. Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis. EMBO J 2001, 20: 792-801.
59. Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J Cell Biol 2002, 157: 1125-37.
60. Leismann O, Lehner CF. Drosophila securin destruction involves a D-box and a KEN-box and promotes anaphase in parallel with Cyclin A degradation. J Cell Sci 2003,116:2453-60.
61. Yanagida M. Cell cycle mechanisms of sister chromatid separation; roles of Cut1/separin and Cut2/securin. Genes Cells 2000, 5: 1-8.
62. Agarwal R, Cohen-Fix O. Phosphorylation of the mitotic regulator Pds1/securin by Cdc28 is required for efficient nuclear localization of Esp1/separase. Genes Dev 2002, 16: 1371-82.
63. Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M and Nasmyth K. An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 1998, 93: 1067-76.
64. Uhlmann F, Lottspeich F and Nasmyth K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 1999, 400: 37-42.
65. Uhlmann F, Wernek W, Poupart MA, Koonin E and Nasmyth K. Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 2000, 103: 375-86.
66. Hauf S, Waizenegger IC and Peters JM. Cohesion cleavage by separase required for anaphase and cytokinesis in human cells. Science 2001, 293: 1320-23.
67. Li Y, Gorbea C, Mahaffey D, Rechsteiner M and Benezra R. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci USA 1997, 94: 12431-6.
68. Fang G, Yu H and Kirschner MW. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 1998, 12: 1871-83.
69. Kim SH, Lin DP, Matsumoto S, Kitazono A and Matsumoto T. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint. Science 1998, 279: 1045-7.
70. Sudakin V, Chan GK T and Yen TJ. Checkpoint inhibition the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, MAD2. J Cell Biol 2001, 154: 925-36.
71. Tang Z, Bharadwaj R, Li B and Yu H. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell 2001, 1: 227-37.
72. Fang G. Checkpoint protein BubRl acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol Biol Cell 2002, 13: 755-66.
73. Ramos-Morales F, Dominguez A, Romero F, Luna R, Multon MC, Pintor-Toro J and Tortolero M. Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene product. Oncogene 2000, 19: 403-9.
74. Yu R, Ren SG, Horwitz GA, Wang Z, Melmed S. Pituitary tumor transforming gene (PTTG) regulates placental JEG-3 cell division and survival: evidence from live cell imaging. Mol Endocrinol 2000, 14: 1137-46.
75. Jallepalli PV, Waizenegger IC, Bunz F, Langer S, Speicher MR, Peters JM, Kinzler K W, Vogelstein B, Lengauer C. Securin is required for chromosomal stability in human cells. Cell 2001,105: 445-57.
76. Wang Z, Yu R, Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol Endocrinol 2001, 15: 1870-9.
77. Mei J, Huang X, Zhang P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. Curr Biol 2001,11:1197-201.
78. Wang Z, Moro E, Kovacs K, Yu R, Melmed S. Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes. Proc Natl Acad Sci U S A 2003, 100: 3428-32.
79. Yu R, Lu W, Chen J, McCabe CJ, Melmed S. Overexpressed pituitary tumor-transforming gene causes aneuploidy in live human cells. Endocrinology 2003, 144: 4991-8.
80. Christopoulou L, Moore JD, Tyler-Smith C. Over-expression of wild-type Securin leads to aneuploidy in human cells. Cancer Lett 2003, 202: 213-8.
81. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 1999, 5: 1317-21.
82. Boelaert K, Tannahill LA, Bulmer JN, Kachilele S, Chan SY, Kim D, Gittoes NJ, Franklyn JA, Kilby MD, McCabe CJ. A potential role for PTTG/securin in the developing human fetal brain. FASEB J 2003, 17: 1631-9.
83. Chien W, Pei L. A novel binding factor facilitates nuclear translocation and transcriptional activation function of the pituitary tumor-transforming gene product. J Biol Chem 2000, 275: 19422-7.
84. McCabe CJ, Boelaert K, Tannahill LA, Heaney AP, Stratford AL, Khaira JS, Hussain S, Sheppard MC, Franklyn JA, Gittoes NJ. Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. J Clin Endocrinol Metab 2002, 87: 4238-44.
85. Ishikawa H, Heaney AP, Yu R, Horwitz GA, Melmed S. Human pituitary tumor-transforming gene induces angiogenesis. J Clin Endocrinol Metab 2000, 86: 867-74.
86. Theodosiou A, Ashworth A. MAP kinase phosphatases. Genome Biol 2002, 3: REVIEWS3009.
87. Hazzalin CA, Mahadevan LC. MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 2002, 3: 30-40.
88. Yang SH, Sharrocks AD, Whitmarsh AJ. Transcriptional regulation by the MAPkinase signaling cascades. Gene 2003, 320: 3-21.
89. Gerthoffer WT, Singer CA. MAPK regulation of gene expression in airway smooth muscle. Respir Physiol Neurobiol 2003, 137: 237-50.
90. Rincon M. MAP-kinase signaling pathways in T cells. Curr Opin Immunol 2001, 13: 339-45.
91. Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol 1999, 71:479-500.
92. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001, 22: 153-83.
93. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001, 410: 37-40.
94. Peter AT, Dhanasekaran N. Apoptosis of granulosa cells: a review on the role of MAPK-signalling modules. Reprod Domest Anim 2003, 38: 209-13.
95. Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J 2000, 14: 2147-57.
96. Pei L. Activation of mitogen-activated protein kinase cascade regulates pituitary tumor-transforming gene transactivation function. J Biol Chem 2000, 275: 31191-8.
97. Pei L. Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J Biol Chem 2001, 276: 8484-91.
98. Bernal JA, Luna R, Espina A, Lazaro I, Ramos-Morales F, Romero F, Arias C, Silva A, Tortolero M, Pintor-Toro JA. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet 2002, 32: 306-11.
99. Zhou Y, Mehta KR, Choi AP, Scolavino S, Zhang X. DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 2003, 278: 462-70.
100. Romero F, Multon MC, Ramos-Morales F, Dominguez A, Bernal JA, Pintor-Toro JA, Tortolero M. Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase. Nucleic Acids Res 2001, 29: 1300-7.
101. Smith GC, Jackson SP. The DNA-dependent protein kinase. Genes Dev 1999, 13: 916-34.
102. Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 1998, 17: 3309-18.
103. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 2000, 14: 2807-12.
104. d'Adda di Fagagna F, Hande MP, Tong WM, Roth D, Lansdorp PM, Wang ZQ, Jackson SP. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol 2001, 11: 1192-6.
105. Lee IA, Seong C, Choe IS. Cloning and expression of human cDNA encoding human homologue of pituitary tumor transforming gene. Biochem Mol Biol Int 1999, 47: 891-897.
106. Morgan DO. Principles of CDK regulation. Nature 1995, 374: 131.
107. Sherr CJ, Kato J, Quelle DE, Matsuoka M, Roussel MF. D-type cyclins and their cyclin-dependent kinases: G1 phase integrators of the mitogenic response. Cold Spring Harb Symp Quant Biol 1994, 59: 11-9.
108. Terada Y, Tatsuka M, Jinno S, Okayama H. Requirement for tyrosine phosphorylation of Cdk4 in Gl arrest induced by ultraviolet irradiation. Nature 1995,376:358-62.
109. Makela TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA. A cyclin associated with the CDK-activating kinase MO15. Nature 1994, 371: 254-7.
110. Morgan DO, Fisher RP, Espinoza FH, Farrell A, Nourse J, Chamberlin H, Jin P. Control of eukaryotic cell cycle progression by phosphorylation of cyclin-dependent kinases. Cancer J Sci Am 1998, 4 Suppl 1: S77-83.
111. Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996, 382: 511-7.
112. Harper JW. Cyclin dependent kinase inhibitors. Cancer Surv 1997, 29: 91-107.
113. Aprelikova O, Xiong Y, Liu ET. Both pl6 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK- activating kinase. J Biol Chem 1995, 270: 18195-7.
114. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D,Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell 1993, 75: 817-25.
115. Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kipl is abrogated by c-Myc. Embo J 1996, 15: 6595-604.
116. Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991, 65: 701-13.
117. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of Gl cyclin-dependent kinases. Cell 1993, 75: 805-16.
118. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997, 1:3-11.
119. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science 1996, 271:1744-7.
120. Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA, Fukasawa K. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclinE overexpression. Oncogene 2000, 19: 1635-46.
121. Lavedan C. The synuclein family. Genome Res 1998, 8: 871-80.
122. George JM. The synucleins. Genome Biology 2001, 3: reviews3002.1 - reviews3002.6
123. Mukaetova-Ladinska EB, Hurt J, Jakes R, Xuereb J, Honer WG, Wischik CM. Alpha-synuclein inclusions in Alzheimer and Lewy body diseases. J Neuropathol Exp Neurol 2000, 5: 408-17.
124. Li JY, Henning Jensen P, Dahlstrom A. Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience 2002, 2: 463-78.
125. Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 1997, 4: 759-64.
126. Ninkina NN, Alimova-Kost MV, Paterson JW, Delaney L, Cohen BB, Imreh S, Gnuchev NV, Davies AM, Buchman VL. Organization, expression and polymorphism??of the human persyn gene. Hum Mol Genet 1998, 7: 1417-24.
127. Jia T, Liu YE, Liu J, Shi YE. Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res 1999, 3: 742-7.
128. Bruening W, Giasson BI, Klein-Szanto AJ, Lee VM, Trojanowski JQ, Godwin AK. Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer 2000, 9: 2154-63.
129. Wu K, Weng Z, Tao Q, Lin G, Wu X, Qian H, Zhang Y, Ding X, Jiang Y, Shi YE. Stage-specific expression of breast cancer-specific gene gamma-synuclein. Cancer Epidemiol Biomarkers Prev 2003, 12: 920-5.
130. Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J. Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 2003, 63: 664-73.
131. Jiang Y, Liu YE, Lu A, Gupta A, Goldberg ID, Liu J, Shi YE. Stimulation of estrogen receptor signaling by gamma synuclein. Cancer Res 2003, 63: 3899-903.
132. Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK. Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J Biol Chem 2002, 277: 35050-60.
133. Surguchov A, Palazzo RE, Surgucheva I. Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. Cell Motil Cytoskeleton 2001, 49: 218-28.
134. Adams RR, Carmene M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends cell boil 2001, 11: 49-54.
135. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic ans amplified in human colotectal cancer. EMBO J 1998, 17: 3052-65.
136. Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S, Otsu M. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 1998, 17: 667-676.
137. Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT.Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity isstimulated by survivin binding and phosphorylation. Mol Biol Cell 2002, 13: 3064-77.
138. Pereira G, Schiebel E. Separase regulates INCENP-Aurora B anaphase spindle function through Cdcl4. Science 2003, 302: 2120-24.
139. Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP, and Survivin in motosis. Mol Biol Cell 2003, 14: 3325-41.
140. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997, 3:917-21.
141. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998, 396: 580-4.
142. Bosher JM, Labouesse M. RNA interference: genetic wand and genetic watchdog. Nat Cell Biol 2000, 2: E31-6.
143. Harmon GJ. RNA interference. Nature 2002, 418: 244-51.
144. Cullen BR. RNA interference: antiviral defense and genetic tool. Nat Immunol 2002,3:597-9.
145. Agami R.RNAi and related mechanisms and their potential use for therapy. Curr Opin Chem Biol 2002, 6: 829-34.
146. Dudley NR, Goldstein B. RNA interference: silencing in the cytoplasm and nucleus. Curr Opin Mol Ther 2003, 5:113-7.
147. Cottrell TR, Doering TL. Silence of the strands: RNA interference in eukaryotic pathogens. Trends Microbiol 2003, 11: 37-43.
148. Kawasaki H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi mediated gene silencing in the cytoplasm of human cells. Nucleic Acids Res 2003, 31: 700-7.
149. Caplen NJ, Fleenor J, Fire A, Morgan RA. dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference. Gene 2000, 252: 95-105.
150. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998,391:806-11.
151. Enders GH. Cyclins in breast cancer: too much of a good thing. Breast Cancer Res 2002,4: 145-7.
152. Motokura T, Arnold A. Cyclin D and oncogenesis. Curr Opin Genet Dev 1993, 3: 5-10.
153. Arnold A. The cyclin D1/PRAD1 oncogene in human neoplasia. J Investig Med 1995,43:543-9.
154. Nichols GE, Williams ME, Gaffey MJ, Stoler MH. Cyclin D1 gene expression in human cervical neoplasia. Mod Pathol 1996, 9: 418-25.
155. Donnellan R, Chetty R. Cyclin D1 and human neoplasia. Mol Pathol 1998, 51:1-7.
156. Osman I, Scher H, Zhang ZF, Soos TJ, Hamza R, Eissa S, Khaled H, Koff A, Cordon-Cardo C. Expression of cyclin D1, but not cyclins E and A, is related to progression in bilharzial bladder cancer. Clin Cancer Res 1997, 3: 2247-51.
157. Arber N, Hibshoosh H, Moss SF, Sutter T, Zhang Y, Begg M, Wang S, Weinstein IB, Holt PR. Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. Gastroenterology 1996, 110: 669-74.
158. Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, El-Naggar A, Hong WK, Hittelman WN. Dysregulated cyclin Dl expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification. Oncogene 1998, 17: 2313-22.
159. Weinstein IB. Relevance of cyclin Dl and other molecular markers to cancer chemoprevention. J Cell Biochem Suppl 1996, 25: 23-8.
160. Dutta A, Chandra R, Leiter LM, Lester S. Cyclins as markers of tumor proliferation: immunocytochemical studies in breast cancer. Proc Natl Acad Sci U S A 1995,92:5386-90.
161. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin Dl ablation. Nature 2001, 411: 1017-21.
162. Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 2001,40: 1117-23.
163. Giodini A, Kallio MJ, Wall NR, Gorbsky GJ, Tognin S, Marchisio PC, Symons M,Altieri DC. Regulation of microtubule stability and mitotic progression by survivin. Cancer Res 2002, 62: 2462-7.
164. Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi F, Santambrogio L, Coggi G, Bosari S. Survivin gene expression in early-stage non-small cell lung cancer. J Pathol 2003, 200: 620-6.
165. Lu CD, Altieri DC, Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 1998, 58: 1808-12.
166. Miyachi K, Sasaki K, Onodera S, Taguchi T, Nagamachi M, Kaneko H, Sunagawa M. Correlation between survivin mRNA expression and lymph node metastasis in gastric cancer. Gastric Cancer 2003, 6: 217-24.
167. Tu SP, Jiang XH, Lin MC, Cui JT, Yang Y, Lum CT, Zou B, Zhu YB, Jiang SH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC. Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 2003, 6: 7724-32.
168. Tanaka K, Iwamoto S, Gon G, Nohara T. Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 2000, 6: 127-34.
169. Kennedy SM, O'Driscoll L, Purcell R, Fitz-Simons N, McDermott EW, Hill AD, O'Higgins NJ, Parkinson M, Linehan R, Clynes M. Prognostic importance of survivin in breast cancer. BrJ Cancer 2003, 88: 1077-83.
170. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 1998,58:5071-4.
171. Kawasaki H, Toyoda M, Shinohara H, Okuda J, Watanabe I, Yamamoto T, Tanaka K, Tenjo T, Tanigawa N. Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer 2001, 91: 2026-32.
172. Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, Nakano T, Suzuki A. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000, 31: 1080-5.
173. Ikeguchi M, Ueda T, Sakatani T, Hirooka Y, Kaibara N. Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma. Diagn Mol Pathol 2002, 11: 33-40.
174. Kato J, Kuwabara Y, Mitani M, Shinoda N, Sato A, Toyama T, Mitsui A, Nishiwaki T, Moriyama S, Kudo J, Fujii Y Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer 2001, 95: 92-5.
175. Swana HS, Grossman D, Anthony JN, Weiss RM, Altieri DC.Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. N Engl J Med 1999,341:452-3.
176. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 2001, 92: 271-8.
177. Yoshida H, Ishiko O, Sumi T, Matsumoto Y, Ogita S. Survivin, bcl-2 and matrix metalloproteinase-2 enhance progression of clear cell- and serous-type ovarian carcinomas. Int J Oncol 2001, 19: 537-42.
178. Grossman D, McNiff JM, Li F, Altieri DC.Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999, 113: 1076-81.
179. Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC. Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. The Lancet 1998, 351: 882-3.
180. Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000, 19: 617-23.
181. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J, Dombret H, Reyes F, Diebold J, Gisselbrecht C, Salles G, Altieri DC, Molina TJ. Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 2000, 96: 1921-5.
182. Adida C, Recher C, Raffoux E, Daniel MT, Taksin AL, Rousselot P, Sigaux F, Degos L, Altieri DC, Dombret H. Expression and prognostic significance of survivin in denovo acute myeloid leukaemia. Br J Haematol 2000, 111: 196-203.
183. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 2000, 60: 6788-93.
184. Ryan KM, Phillips AC, Vousden KH. Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 2001, 13: 332-7.
185. Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol 2002, 14:86-91.
186. Albrechtsen N, Dornreiter I, Grosse F, Kim E, Wiesmuller L, Deppert W. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 1999, 18: 7706-17.
187. Miller JR. The Wnts. Genome Biol 2002, 3: REVIEWS3001.
188. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev 1997,11:3286-305.
189. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 2000, 287: 1606-9.
190. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000, 103: 311-20.
191. Polakis P. Wnt signaling and cancer. Genes Dev 2000, 14: 1837-51.
192. van Es JH, Barker N, Clevers H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 2003, 13: 28-33.
193. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science 1998,281: 1509-12.
194. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature1999, 398: 422-6.
195. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. The cyclin Dl gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 1999,96: 5522-7.
196. Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM. The metalloproteinase matrilysin is a target of beta-catenintransactivation in intestinal tumors. Oncogene 1999, 18: 2883-91.
197. Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T, Clevers H. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 1999,285: 1923-6.
198. He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999, 99: 335-45.
199. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 2000, 14: 585-95.
200. Koh TJ, Bulitta CJ, Fleming JV, Dockray GJ. Varro A, Wang TC. Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest 2000, 106: 533-9.
201. Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S. Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Cancer Res 2000, 60: 4761-6.
202. Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C, Garcia PD, Randazzo FM, et al. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors. Proc Natl Acad Sci U S A 2001, 98. 14973-8.
203. Zhang T, Otevrel T, Gao Z, Ehrlich SM, Fields JZ, Boman BM. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 2001, 61: 8664-7.
204. Rockman SP, Currie SA, Ciavarella M, Vincan E, Dow C, Thomas RJ, Phillips WA. Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J Biol Chem 2001, 276: 45113-9.
205. Kolligs FT, Nieman MT, Winer I, Hu G, Van Mater D, Feng Y, Smith IM, Wu R, Zhai Y, Cho KR, Fearon ER. ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell 2002, 1: 145-55.
206. Shimokawa T, Furukawa Y, Sakai M, Li M, Miwa N, Lin Y M, Nakamura Y. Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex. Cancer Res 2003, 63: 6116-20.
207. Nakamura Y. Cleaning up on beta-catenin. Nat Med 1997, 3: 499-500.
208. Gumbiner BM. Signal transduction of beta-catenin. Curr Opin Cell Biol 1995, 7: 634-40.
209. Alexander N, Wong CS, Pignatelli M. β-catenin--A linchpin in colorectal carcinogenesis. Am J Pathol 2002,160: 389-401.
210. Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci. 1999, 56: 523-37.
211. Akiyama T. Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 2000, 11: 273-82.
212. van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 1997, 88: 789-99.
213. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996,382:638-42.
214. Brantjes H, Barker N, van Es J, Clevers H.TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 2002, 383: 255-61.
215. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995, 378: 785-9.
216. Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinosi-tol 3-Kinase/Akt cell survival pathway. J Biol Chem 1998, 273: 19929-32.
217. Bijur GN, De Sarno P, Jope RS. Glycogen synthase kinase-3β facilitates staurospor-ine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 2000, 275: 7583-90.
218. Nikolakaki E, Coffer PJ, Hemelsoet R, Woodgett JR, Defize LH. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their trans-aetivating potential in intact cells. Oncogene 1993, 8: 833-40.
219. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000, 14: 2501-14.
220. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3β regulates eyelin D1 proteolysis and subcellular localization. Genes Dev 1998, 12: 3499-511.
221. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 2003, 22: 395-403.
222. Shapiro P. Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy. Crit Rev Clin Lab Sci 2002, 39: 285-330.
223. Santen RJ, Song RX, McPherson R, Kumar R, Adam L, Jeng MH, Yue W. The role of mitogen-activated protein(MAP) kinase in breast cancer, J Steroid Biochem Mol Biol 2002, 80: 239-56.
224. Li LD, Lu FZ, Zhang SW, Mu R, Sun XD, Huan-Pu XM, Sun J, Zhou YS, Ou-Yang NH, Rao KQ, Chen YD, Sun AM, Xue ZF, Xia Y. The death epidemiology analysis of malignancy in china in 1990-1992. Chinese J oncol 1996, 18: 403-7.
225. Parkin M. Global cancer statistics in the year 2000. The Lancet 2001, 2: 533-43.
226. Kimura Y, Shiozaki H, Doki Y, Yamamoto M, Utsunomiya T, Kawanishi K, Fukuchi N, Inoue M, Tsujinaka T, Monden M. Cytoplasmic beta-catenin in esophageal cancers. Int J Cancer 1999, 84: 174-8.
227. Ninomiya I, Endo Y, Fushida S, Sasagawa T, Miyashita T, Fujimura T, Nishimura G, Tani T, Hashimoto T, Yagi M, Shimizu K, Ohta T, et al. Alteration of beta-catenin expression in esophageal squamous-cell carcinoma. Int J Cancer 2000, 85: 757-61.
228．周晓波，吕宁，张维等Beta-连环蛋白在食管癌组织中的表达及意义。癌症2002，21：877-80．