Identifizierung neuer E2F-Zielgene in der Wachstumskontrolle und TumorprogressionDipl. Biol. Caroline SchreiberZusammenfassung1121.131.24432#2551.2.151.2.26550#3807430#1891.2.381.2.41.2.59101.311575#128121.413434#313141.4.1287#1501.4.1.1151.4.1.2161.4.1.31.4.1.4171.4.21.4.318191.522.120512#384212.222456#3842.323459#5382.424476#422252.526434#384272.628438#4802930375#1782.731559#35332555#309332.834547#373352.936387#672372.102.10.1382.10.2545#198392.10.340561#3252.10.441575#307572#308423423.1433.2443.3453.4463.547483.6493.75051427#24744.14.1.1514.1.2524.1.34.1.4534.24.2.14.2.2544.2.3554.2.456574.2.54.2.658594.34.3.14.3.2604.3.34.3.44.44.4.1614.4.24.4.34.4.4624.4.54.4.6634.4.74.4.84.4.9644.4.104.4.1165AnhangAbkürzungsverzeichnisLiteraturverzeichnisErklärungPublikationslistedeInhaltsverzeichnisHilfe Literaturverzeichnis [1] Vogelstein, B. and Kinzler, K. W. (1993): The multistep nature of cancer, Trends Genet, (vol. 9), No. 4, pp.138-41. [2] Hanahan, D. and Weinberg, R. A. (2000): The hallmarks of cancer, Cell, (vol. 100), No. 1, pp.57-70. [3] Sherr, C. J. and Roberts, J. M. (1995): Inhibitors of mammalian G1 cyclin-dependent kinases, Genes Dev, (vol. 9), No. 10, pp.1149-63. [4] Edgar, B. A. and Lehner, C. F. (1996): Developmental control of cell cycle regulators: a fly's perspective, Science, (vol. 274), No. 5293, pp.1646-52. [5] Massague, J. (2004): G1 cell-cycle control and cancer, Nature, (vol. 432), No. 7015, pp.298-306. [6] Pardee, A. B. (1974): A restriction point for control of normal animal cell proliferation, Proc Natl Acad Sci U S A, (vol. 71), No. 4, pp.1286-90. [7] Gad, A.; Thullberg, M.; Dannenberg, J. H.; te Riele, H. and Stromblad, S. (2004): Retinoblastoma susceptibility gene product (pRb) and p107 functionally separate the requirements for serum and anchorage in the cell cycle G1-phase, J Biol Chem, (vol. 279), No. 14, pp.13640-4. [8] Larsson, O.; Zetterberg, A. and Engstrom, W. (1985): Cell-cycle-specific induction of quiescence achieved by limited inhibition of protein synthesis: counteractive effect of addition of purified growth factors, J Cell Sci, (vol. 73), pp.375-87. [9] Hayflick, L. and Moorhead, P. S. (1961): The serial cultivation of human diploid cell strains, Exp Cell Res, (vol. 25), pp.585-621. [10] Hayflick, L. (1965): The Limited in Vitro Lifetime of Human Diploid Cell Strains, Exp Cell Res, (vol. 37), pp.614-36. [11] Campisi, J. and d'Adda di Fagagna, F. (2007): Cellular senescence: when bad things happen to good cells, Nat Rev Mol Cell Biol, (vol. 8), No. 9, pp.729-40. [12] Pledger, W. J.; Stiles, C. D.; Antoniades, H. N. and Scher, C. D. (1977): Induction of DNA synthesis in BALB/c 3T3 cells by serum components: reevaluation of the commitment process, Proc Natl Acad Sci U S A, (vol. 74), No. 10, pp.4481-5. [13] Sherr, C. J. and McCormick, F. (2002): The RB and p53 pathways in cancer, Cancer Cell, (vol. 2), No. 2, pp.103-12. [14] Dowdy, S. F.; Hinds, P. W.; Louie, K.; Reed, S. I.; Arnold, A. and Weinberg, R. A. (1993): Physical interaction of the retinoblastoma protein with human D cyclins, Cell, (vol. 73), No. 3, pp.499-511. [15] Sherr, C. J. and Roberts, J. M. (1999): CDK inhibitors: positive and negative regulators of G1-phase progression, Genes Dev, (vol. 13), No. 12, pp.1501-12. [16] Kaelin, W. G., Jr.; Ewen, M. E. and Livingston, D. M. (1990): Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product, Mol Cell Biol, (vol. 10), No. 7, pp.3761-9. [17] Kaelin, W. G., Jr.; Pallas, D. C.; DeCaprio, J. A.; Kaye, F. J. and Livingston, D. M. (1991): Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product, Cell, (vol. 64), No. 3, pp.521-32. [18] Mulligan, G. and Jacks, T. (1998): The retinoblastoma gene family: cousins with overlapping interests, Trends Genet, (vol. 14), No. 6, pp.223-9. [19] Trimarchi, J. M. and Lees, J. A. (2002): Sibling rivalry in the E2F family, Nat Rev Mol Cell Biol, (vol. 3), No. 1, pp.11-20. [20] Flemington, E. K.; Speck, S. H. and Kaelin, W. G., Jr. (1993): E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product, Proc Natl Acad Sci U S A, (vol. 90), No. 15, pp.6914-8. [21] Magnaghi-Jaulin, L.; Groisman, R.; Naguibneva, I.; Robin, P.; Lorain, S.; Le Villain, J. P.; Troalen, F.; Trouche, D. and Harel-Bellan, A. (1998): Retinoblastoma protein represses transcription by recruiting a histone deacetylase, Nature, (vol. 391), No. 6667, pp.601-5. [22] Brehm, A.; Miska, E. A.; McCance, D. J.; Reid, J. L.; Bannister, A. J. and Kouzarides, T. (1998): Retinoblastoma protein recruits histone deacetylase to repress transcription, Nature, (vol. 391), No. 6667, pp.597-601. [23] Zhang, H. S.; Gavin, M.; Dahiya, A.; Postigo, A. A.; Ma, D.; Luo, R. X.; Harbour, J. W. and Dean, D. C. (2000): Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF, Cell, (vol. 101), No. 1, pp.79-89. [24] Rayman, J. B.; Takahashi, Y.; Indjeian, V. B.; Dannenberg, J. H.; Catchpole, S.; Watson, R. J.; te Riele, H. and Dynlacht, B. D. (2002): E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex, Genes Dev, (vol. 16), No. 8, pp.933-47. [25] Nagl, N. G., Jr.; Wang, X.; Patsialou, A.; Van Scoy, M. and Moran, E. (2007): Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control, Embo J, (vol. 26), No. 3, pp.752-63. [26] Ewen, M. E.; Sluss, H. K.; Sherr, C. J.; Matsushime, H.; Kato, J. and Livingston, D. M. (1993): Functional interactions of the retinoblastoma protein with mammalian D-type cyclins, Cell, (vol. 73), No. 3, pp.487-97. [27] Kato, J.; Matsushime, H.; Hiebert, S. W.; Ewen, M. E. and Sherr, C. J. (1993): Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4, Genes Dev, (vol. 7), No. 3, pp.331-42. [28] Giacinti, C. and Giordano, A. (2006): RB and cell cycle progression, Oncogene, (vol. 25), No. 38, pp.5220-7. [29] Weinberg, R. A. (1995): The retinoblastoma protein and cell cycle control, Cell, (vol. 81), No. 3, pp.323-30. [30] Takahashi, Y.; Rayman, J. B. and Dynlacht, B. D. (2000): Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression, Genes Dev, (vol. 14), No. 7, pp.804-16. [31] Taubert, S.; Gorrini, C.; Frank, S. R.; Parisi, T.; Fuchs, M.; Chan, H. M.; Livingston, D. M. and Amati, B. (2004): E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1, Mol Cell Biol, (vol. 24), No. 10, pp.4546-56. [32] Tyagi, S.; Chabes, A. L.; Wysocka, J. and Herr, W. (2007): E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases, Mol Cell, (vol. 27), No. 1, pp.107-19. [33] Blais, A. and Dynlacht, B. D. (2007): E2F-associated chromatin modifiers and cell cycle control, Curr Opin Cell Biol, (vol. 19), No. 6, pp.658-62. [34] Benedict, W. F.; Murphree, A. L.; Banerjee, A.; Spina, C. A.; Sparkes, M. C. and Sparkes, R. S. (1983): Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene, Science, (vol. 219), No. 4587, pp.973-5. [35] Sparkes, R. S.; Murphree, A. L.; Lingua, R. W.; Sparkes, M. C.; Field, L. L.; Funderburk, S. J. and Benedict, W. F. (1983): Gene for hereditary retinoblastoma assigned to human chromosome 13 by linkage to esterase D, Science, (vol. 219), No. 4587, pp.971-3. [36] Godbout, R.; Dryja, T. P.; Squire, J.; Gallie, B. L. and Phillips, R. A. (1983): Somatic inactivation of genes on chromosome 13 is a common event in retinoblastoma, Nature, (vol. 304), No. 5925, pp.451-3. [37] Knudson, A. G., Jr. (1971): Mutation and cancer: statistical study of retinoblastoma, Proc Natl Acad Sci U S A, (vol. 68), No. 4, pp.820-3. [38] Matsunaga, E. (1980): On estimating penetrance of the retinoblastoma gene, Hum Genet, (vol. 56), No. 1, pp.127-8. [39] Goodrich, D. W. and Lee, W. H. (1993): Molecular characterization of the retinoblastoma susceptibility gene, Biochim Biophys Acta, (vol. 1155), No. 1, pp.43-61. [40] Harbour, J. W.; Lai, S. L.; Whang-Peng, J.; Gazdar, A. F.; Minna, J. D. and Kaye, F. J. (1988): Abnormalities in structure and expression of the human retinoblastoma gene in SCLC, Science, (vol. 241), No. 4863, pp.353-7. [41] Horowitz, J. M.; Park, S. H.; Bogenmann, E.; Cheng, J. C.; Yandell, D. W.; Kaye, F. J.; Minna, J. D.; Dryja, T. P. and Weinberg, R. A. (1990): Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells, Proc Natl Acad Sci U S A, (vol. 87), No. 7, pp.2775-9. [42] Wadayama, B.; Toguchida, J.; Shimizu, T.; Ishizaki, K.; Sasaki, M. S.; Kotoura, Y. and Yamamuro, T. (1994): Mutation spectrum of the retinoblastoma gene in osteosarcomas, Cancer Res, (vol. 54), No. 11, pp.3042-8. [43] Nielsen, N. H.; Loden, M.; Cajander, J.; Emdin, S. O. and Landberg, G. (1999): G1-S transition defects occur in most breast cancers and predict outcome, Breast Cancer Res Treat, (vol. 56), No. 2, pp.105-12. [44] Dunn, J. M.; Phillips, R. A.; Becker, A. J. and Gallie, B. L. (1988): Identification of germline and somatic mutations affecting the retinoblastoma gene, Science, (vol. 241), No. 4874, pp.1797-800. [45] Kamb, A.; Shattuck-Eidens, D.; Eeles, R.; Liu, Q.; Gruis, N. A.; Ding, W.; Hussey, C.; Tran, T.; Miki, Y.; Weaver-Feldhaus, J. and et al. (1994): Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus, Nat Genet, (vol. 8), No. 1, pp.23-6. [46] Ruas, M. and Peters, G. (1998): The p16INK4a/CDKN2A tumor suppressor and its relatives, Biochim Biophys Acta, (vol. 1378), No. 2, pp.F115-77. [47] Liu, H.; Dibling, B.; Spike, B.; Dirlam, A. and Macleod, K. (2004): New roles for the RB tumor suppressor protein, Curr Opin Genet Dev, (vol. 14), No. 1, pp.55-64. [48] Jacks, T.; Fazeli, A.; Schmitt, E. M.; Bronson, R. T.; Goodell, M. A. and Weinberg, R. A. (1992): Effects of an Rb mutation in the mouse, Nature, (vol. 359), No. 6393, pp.295-300. [49] Lee, M. H.; Williams, B. O.; Mulligan, G.; Mukai, S.; Bronson, R. T.; Dyson, N.; Harlow, E. and Jacks, T. (1996): Targeted disruption of p107: functional overlap between p107 and Rb, Genes Dev, (vol. 10), No. 13, pp.1621-32. [50] Dannenberg, J. H.; Schuijff, L.; Dekker, M.; van der Valk, M. and te Riele, H. (2004): Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130, Genes Dev, (vol. 18), No. 23, pp.2952-62. [51] MacPherson, D.; Sage, J.; Kim, T.; Ho, D.; McLaughlin, M. E. and Jacks, T. (2004): Cell type-specific effects of Rb deletion in the murine retina, Genes Dev, (vol. 18), No. 14, pp.1681-94. [52] Wikenheiser-Brokamp, K. A. (2004): Rb family proteins differentially regulate distinct cell lineages during epithelial development, Development, (vol. 131), No. 17, pp.4299-310. [53] Wu, L.; de Bruin, A.; Saavedra, H. I.; Starovic, M.; Trimboli, A.; Yang, Y.; Opavska, J.; Wilson, P.; Thompson, J. C.; Ostrowski, M. C.; Rosol, T. J.; Woollett, L. A.; Weinstein, M.; Cross, J. C.; Robinson, M. L. and Leone, G. (2003): Extra-embryonic function of Rb is essential for embryonic development and viability, Nature, (vol. 421), No. 6926, pp.942-7. [54] Lee, E. Y.; Chang, C. Y.; Hu, N.; Wang, Y. C.; Lai, C. C.; Herrup, K.; Lee, W. H. and Bradley, A. (1992): Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis, Nature, (vol. 359), No. 6393, pp.288-94. [55] Clarke, A. R.; Maandag, E. R.; van Roon, M.; van der Lugt, N. M.; van der Valk, M.; Hooper, M. L.; Berns, A. and te Riele, H. (1992): Requirement for a functional Rb-1 gene in murine development, Nature, (vol. 359), No. 6393, pp.328-30. [56] Almasan, A.; Yin, Y.; Kelly, R. E.; Lee, E. Y.; Bradley, A.; Li, W.; Bertino, J. R. and Wahl, G. M. (1995): Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis, Proc Natl Acad Sci U S A, (vol. 92), No. 12, pp.5436-40. [57] Herrera, R. E.; Sah, V. P.; Williams, B. O.; Makela, T. P.; Weinberg, R. A. and Jacks, T. (1996): Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts, Mol Cell Biol, (vol. 16), No. 5, pp.2402-7. [58] Hurford, R. K., Jr.; Cobrinik, D.; Lee, M. H. and Dyson, N. (1997): pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes, Genes Dev, (vol. 11), No. 11, pp.1447-63. [59] Sage, J.; Mulligan, G. J.; Attardi, L. D.; Miller, A.; Chen, S.; Williams, B.; Theodorou, E. and Jacks, T. (2000): Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization, Genes Dev, (vol. 14), No. 23, pp.3037-50. [60] Dannenberg, J. H.; van Rossum, A.; Schuijff, L. and te Riele, H. (2000): Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions, Genes Dev, (vol. 14), No. 23, pp.3051-64. [61] Kovesdi, I.; Reichel, R. and Nevins, J. R. (1986): Identification of a cellular transcription factor involved in E1A trans-activation, Cell, (vol. 45), No. 2, pp.219-28. [62] Reichel, R.; Kovesdi, I. and Nevins, J. R. (1987): Developmental control of a promoter-specific factor that is also regulated by the E1A gene product, Cell, (vol. 48), No. 3, pp.501-6. [63] Bagchi, S.; Weinmann, R. and Raychaudhuri, P. (1991): The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F, Cell, (vol. 65), No. 6, pp.1063-72. [64] Bandara, L. R. and La Thangue, N. B. (1991): Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor, Nature, (vol. 351), No. 6326, pp.494-7. [65] Chellappan, S. P.; Hiebert, S.; Mudryj, M.; Horowitz, J. M. and Nevins, J. R. (1991): The E2F transcription factor is a cellular target for the RB protein, Cell, (vol. 65), No. 6, pp.1053-61. [66] Chittenden, T.; Livingston, D. M. and Kaelin, W. G., Jr. (1991): The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein, Cell, (vol. 65), No. 6, pp.1073-82. [67] Whyte, P.; Buchkovich, K. J.; Horowitz, J. M.; Friend, S. H.; Raybuck, M.; Weinberg, R. A. and Harlow, E. (1988): Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product, Nature, (vol. 334), No. 6178, pp.124-9. [68] Dyson, N.; Howley, P. M.; Munger, K. and Harlow, E. (1989): The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product, Science, (vol. 243), No. 4893, pp.934-7. [69] Munger, K.; Werness, B. A.; Dyson, N.; Phelps, W. C.; Harlow, E. and Howley, P. M. (1989): Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product, Embo J, (vol. 8), No. 13, pp.4099-105. [70] Girling, R.; Partridge, J. F.; Bandara, L. R.; Burden, N.; Totty, N. F.; Hsuan, J. J. and La Thangue, N. B. (1993): A new component of the transcription factor DRTF1/E2F, Nature, (vol. 362), No. 6415, pp.83-7. [71] Dynlacht, B. D.; Brook, A.; Dembski, M.; Yenush, L. and Dyson, N. (1994): DNA-binding and trans-activation properties of Drosophila E2F and DP proteins, Proc Natl Acad Sci U S A, (vol. 91), No. 14, pp.6359-63. [72] Ohtani, K. and Nevins, J. R. (1994): Functional properties of a Drosophila homolog of the E2F1 gene, Mol Cell Biol, (vol. 14), No. 3, pp.1603-12. [73] Sawado, T.; Yamaguchi, M.; Nishimoto, Y.; Ohno, K.; Sakaguchi, K. and Matsukage, A. (1998): dE2F2, a novel E2F-family transcription factor in Drosophila melanogaster, Biochem Biophys Res Commun, (vol. 251), No. 2, pp.409-15. [74] Lu, X. and Horvitz, H. R. (1998): lin-35 and lin-53, two genes that antagonize a C. elegans Ras pathway, encode proteins similar to Rb and its binding protein RbAp48, Cell, (vol. 95), No. 7, pp.981-91. [75] Shen, W. H. (2002): The plant E2F-Rb pathway and epigenetic control, Trends Plant Sci, (vol. 7), No. 11, pp.505-11. [76] Page, B. D.; Guedes, S.; Waring, D. and Priess, J. R. (2001): The C. elegans E2F- and DP-related proteins are required for embryonic asymmetry and negatively regulate Ras/MAPK signaling, Mol Cell, (vol. 7), No. 3, pp.451-60. [77] Bracken, A. P.; Ciro, M.; Cocito, A. and Helin, K. (2004): E2F target genes: unraveling the biology, Trends Biochem Sci, (vol. 29), No. 8, pp.409-17. [78] Zheng, N.; Fraenkel, E.; Pabo, C. O. and Pavletich, N. P. (1999): Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP, Genes Dev, (vol. 13), No. 6, pp.666-74. [79] Di Stefano, L.; Jensen, M. R. and Helin, K. (2003): E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes, Embo J, (vol. 22), No. 23, pp.6289-98. [80] de Bruin, A.; Maiti, B.; Jakoi, L.; Timmers, C.; Buerki, R. and Leone, G. (2003): Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation, J Biol Chem, (vol. 278), No. 43, pp.42041-9. [81] Li, J.; Ran, C.; Li, E.; Gordon, F.; Comstock, G.; Siddiqui, H.; Cleghorn, W.; Chen, H. Z.; Kornacker, K.; Liu, C. G.; Pandit, S. K.; Khanizadeh, M.; Weinstein, M.; Leone, G. and de Bruin, A. (2008): Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development, Dev Cell, (vol. 14), No. 1, pp.62-75. [82] Helin, K.; Wu, C. L.; Fattaey, A. R.; Lees, J. A.; Dynlacht, B. D.; Ngwu, C. and Harlow, E. (1993): Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation, Genes Dev, (vol. 7), No. 10, pp.1850-61. [83] Bandara, L. R.; Buck, V. M.; Zamanian, M.; Johnston, L. H. and La Thangue, N. B. (1993): Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F, Embo J, (vol. 12), No. 11, pp.4317-24. [84] Helin, K.; Harlow, E. and Fattaey, A. (1993): Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein, Mol Cell Biol, (vol. 13), No. 10, pp.6501-8. [85] Morkel, M.; Wenkel, J.; Bannister, A. J.; Kouzarides, T. and Hagemeier, C. (1997): An E2F-like repressor of transcription, Nature, (vol. 390), No. 6660, pp.567-8. [86] Attwooll, C.; Lazzerini Denchi, E. and Helin, K. (2004): The E2F family: specific functions and overlapping interests, Embo J, (vol. 23), No. 24, pp.4709-16. [87] Trimarchi, J. M.; Fairchild, B.; Wen, J. and Lees, J. A. (2001): The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex, Proc Natl Acad Sci U S A, (vol. 98), No. 4, pp.1519-24. [88] Ogawa, H.; Ishiguro, K.; Gaubatz, S.; Livingston, D. M. and Nakatani, Y. (2002): A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells, Science, (vol. 296), No. 5570, pp.1132-6. [89] Dyson, N. (1998): The regulation of E2F by pRB-family proteins, Genes Dev, (vol. 12), No. 15, pp.2245-62. [90] Shirodkar, S.; Ewen, M.; DeCaprio, J. A.; Morgan, J.; Livingston, D. M. and Chittenden, T. (1992): The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner, Cell, (vol. 68), No. 1, pp.157-66. [91] Ikeda, M. A.; Jakoi, L. and Nevins, J. R. (1996): A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation, Proc Natl Acad Sci U S A, (vol. 93), No. 8, pp.3215-20. [92] Moberg, K.; Starz, M. A. and Lees, J. A. (1996): E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry, Mol Cell Biol, (vol. 16), No. 4, pp.1436-49. [93] Magae, J.; Wu, C. L.; Illenye, S.; Harlow, E. and Heintz, N. H. (1996): Nuclear localization of DP and E2F transcription factors by heterodimeric partners and retinoblastoma protein family members, J Cell Sci, (vol. 109 ( Pt 7)), pp.1717-26. [94] Gaubatz, S.; Lees, J. A.; Lindeman, G. J. and Livingston, D. M. (2001): E2F4 is exported from the nucleus in a CRM1-dependent manner, Mol Cell Biol, (vol. 21), No. 4, pp.1384-92. [95] Muller, H.; Moroni, M. C.; Vigo, E.; Petersen, B. O.; Bartek, J. and Helin, K. (1997): Induction of S-phase entry by E2F transcription factors depends on their nuclear localization, Mol Cell Biol, (vol. 17), No. 9, pp.5508-20. [96] Verona, R.; Moberg, K.; Estes, S.; Starz, M.; Vernon, J. P. and Lees, J. A. (1997): E2F activity is regulated by cell cycle-dependent changes in subcellular localization, Mol Cell Biol, (vol. 17), No. 12, pp.7268-82. [97] Xu, M.; Sheppard, K. A.; Peng, C. Y.; Yee, A. S. and Piwnica-Worms, H. (1994): Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation, Mol Cell Biol, (vol. 14), No. 12, pp.8420-31. [98] Hiebert, S. W.; Lipp, M. and Nevins, J. R. (1989): E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor, Proc Natl Acad Sci U S A, (vol. 86), No. 10, pp.3594-8. [99] Thalmeier, K.; Synovzik, H.; Mertz, R.; Winnacker, E. L. and Lipp, M. (1989): Nuclear factor E2F mediates basic transcription and trans-activation by E1a of the human MYC promoter, Genes Dev, (vol. 3), No. 4, pp.527-36. [100] Blake, M. C. and Azizkhan, J. C. (1989): Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo, Mol Cell Biol, (vol. 9), No. 11, pp.4994-5002. [101] Schulze, A.; Zerfass, K.; Spitkovsky, D.; Middendorp, S.; Berges, J.; Helin, K.; Jansen-Durr, P. and Henglein, B. (1995): Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site, Proc Natl Acad Sci U S A, (vol. 92), No. 24, pp.11264-8. [102] Tommasi, S. and Pfeifer, G. P. (1995): In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression, Mol Cell Biol, (vol. 15), No. 12, pp.6901-13. [103] Cress, W. D. and Nevins, J. R. (1996): Use of the E2F transcription factor by DNA tumor virus regulatory proteins, Curr Top Microbiol Immunol, (vol. 208), pp.63-78. [104] Muller, H.; Bracken, A. P.; Vernell, R.; Moroni, M. C.; Christians, F.; Grassilli, E.; Prosperini, E.; Vigo, E.; Oliner, J. D. and Helin, K. (2001): E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis, Genes Dev, (vol. 15), No. 3, pp.267-85. [105] Ishida, S.; Huang, E.; Zuzan, H.; Spang, R.; Leone, G.; West, M. and Nevins, J. R. (2001): Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis, Mol Cell Biol, (vol. 21), No. 14, pp.4684-99. [106] Ren, B.; Cam, H.; Takahashi, Y.; Volkert, T.; Terragni, J.; Young, R. A. and Dynlacht, B. D. (2002): E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints, Genes Dev, (vol. 16), No. 2, pp.245-56. [107] Huang, E.; Ishida, S.; Pittman, J.; Dressman, H.; Bild, A.; Kloos, M.; D'Amico, M.; Pestell, R. G.; West, M. and Nevins, J. R. (2003): Gene expression phenotypic models that predict the activity of oncogenic pathways, Nat Genet, (vol. 34), No. 2, pp.226-30. [108] Black, E. P.; Hallstrom, T.; Dressman, H. K.; West, M. and Nevins, J. R. (2005): Distinctions in the specificity of E2F function revealed by gene expression signatures, Proc Natl Acad Sci U S A, (vol. 102), No. 44, pp.15948-53. [109] DeGregori, J. (2002): The genetics of the E2F family of transcription factors: shared functions and unique roles, Biochim Biophys Acta, (vol. 1602), No. 2, pp.131-50. [110] DeGregori, J.; Leone, G.; Ohtani, K.; Miron, A. and Nevins, J. R. (1995): E2F-1 accumulation bypasses a G1 arrest resulting from the inhibition of G1 cyclin-dependent kinase activity, Genes Dev, (vol. 9), No. 23, pp.2873-87. [111] Singh, P.; Wong, S. H. and Hong, W. (1994): Overexpression of E2F-1 in rat embryo fibroblasts leads to neoplastic transformation, Embo J, (vol. 13), No. 14, pp.3329-38. [112] Xu, G.; Livingston, D. M. and Krek, W. (1995): Multiple members of the E2F transcription factor family are the products of oncogenes, Proc Natl Acad Sci U S A, (vol. 92), No. 5, pp.1357-61. [113] Pierce, A. M.; Fisher, S. M.; Conti, C. J. and Johnson, D. G. (1998): Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in skin tumor development, Oncogene, (vol. 16), No. 10, pp.1267-76. [114] Vigo, E.; Muller, H.; Prosperini, E.; Hateboer, G.; Cartwright, P.; Moroni, M. C. and Helin, K. (1999): CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase, Mol Cell Biol, (vol. 19), No. 9, pp.6379-95. [115] Yamasaki, L.; Bronson, R.; Williams, B. O.; Dyson, N. J.; Harlow, E. and Jacks, T. (1998): Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice, Nat Genet, (vol. 18), No. 4, pp.360-4. [116] Ziebold, U.; Reza, T.; Caron, A. and Lees, J. A. (2001): E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos, Genes Dev, (vol. 15), No. 4, pp.386-91. [117] DeGregori, J.; Leone, G.; Miron, A.; Jakoi, L. and Nevins, J. R. (1997): Distinct roles for E2F proteins in cell growth control and apoptosis, Proc Natl Acad Sci U S A, (vol. 94), No. 14, pp.7245-50. [118] Lazzerini Denchi, E. and Helin, K. (2005): E2F1 is crucial for E2F-dependent apoptosis, EMBO Rep, (vol. 6), No. 7, pp.661-8. [119] Opavsky, R.; Tsai, S. Y.; Guimond, M.; Arora, A.; Opavska, J.; Becknell, B.; Kaufmann, M.; Walton, N. A.; Stephens, J. A.; Fernandez, S. A.; Muthusamy, N.; Felsher, D. W.; Porcu, P.; Caligiuri, M. A. and Leone, G. (2007): Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis, Proc Natl Acad Sci U S A, (vol. 104), No. 39, pp.15400-5. [120] Yamasaki, L.; Jacks, T.; Bronson, R.; Goillot, E.; Harlow, E. and Dyson, N. J. (1996): Tumor induction and tissue atrophy in mice lacking E2F-1, Cell, (vol. 85), No. 4, pp.537-48. [121] Field, S. J.; Tsai, F. Y.; Kuo, F.; Zubiaga, A. M.; Kaelin, W. G., Jr.; Livingston, D. M.; Orkin, S. H. and Greenberg, M. E. (1996): E2F-1 functions in mice to promote apoptosis and suppress proliferation, Cell, (vol. 85), No. 4, pp.549-61. [122] Ziebold, U.; Lee, E. Y.; Bronson, R. T. and Lees, J. A. (2003): E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas, Mol Cell Biol, (vol. 23), No. 18, pp.6542-52. [123] Lees, J. A.; Saito, M.; Vidal, M.; Valentine, M.; Look, T.; Harlow, E.; Dyson, N. and Helin, K. (1993): The retinoblastoma protein binds to a family of E2F transcription factors, Mol Cell Biol, (vol. 13), No. 12, pp.7813-25. [124] Leone, G.; Nuckolls, F.; Ishida, S.; Adams, M.; Sears, R.; Jakoi, L.; Miron, A. and Nevins, J. R. (2000): Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins, Mol Cell Biol, (vol. 20), No. 10, pp.3626-32. [125] Adams, M. R.; Sears, R.; Nuckolls, F.; Leone, G. and Nevins, J. R. (2000): Complex transcriptional regulatory mechanisms control expression of the E2F3 locus, Mol Cell Biol, (vol. 20), No. 10, pp.3633-9. [126] Leone, G.; DeGregori, J.; Yan, Z.; Jakoi, L.; Ishida, S.; Williams, R. S. and Nevins, J. R. (1998): E2F3 activity is regulated during the cell cycle and is required for the induction of S phase, Genes Dev, (vol. 12), No. 14, pp.2120-30. [127] Humbert, P. O.; Verona, R.; Trimarchi, J. M.; Rogers, C.; Dandapani, S. and Lees, J. A. (2000): E2f3 is critical for normal cellular proliferation, Genes Dev, (vol. 14), No. 6, pp.690-703. [128] Wu, L.; Timmers, C.; Maiti, B.; Saavedra, H. I.; Sang, L.; Chong, G. T.; Nuckolls, F.; Giangrande, P.; Wright, F. A.; Field, S. J.; Greenberg, M. E.; Orkin, S.; Nevins, J. R.; Robinson, M. L. and Leone, G. (2001): The E2F1-3 transcription factors are essential for cellular proliferation, Nature, (vol. 414), No. 6862, pp.457-62. [129] Aslanian, A. (2005): Crosstalk between E2F3 and p19ARF7p53 in the regulation of cell cycle progression and tumorigenesis. [130] Aslanian, A.; Iaquinta, P. J.; Verona, R. and Lees, J. A. (2004): Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics, Genes Dev, (vol. 18), No. 12, pp.1413-22. [131] Sharma, N.; Timmers, C.; Trikha, P.; Saavedra, H. I.; Obery, A. and Leone, G. (2006): Control of the p53-p21CIP1 Axis by E2f1, E2f2, and E2f3 is essential for G1/S progression and cellular transformation, J Biol Chem, (vol. 281), No. 47, pp.36124-31. [132] Timmers, C.; Sharma, N.; Opavsky, R.; Maiti, B.; Wu, L.; Wu, J.; Orringer, D.; Trikha, P.; Saavedra, H. I. and Leone, G. (2007): E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop, Mol Cell Biol, (vol. 27), No. 1, pp.65-78. [133] Schlisio, S.; Halperin, T.; Vidal, M. and Nevins, J. R. (2002): Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function, Embo J, (vol. 21), No. 21, pp.5775-86. [134] Giangrande, P. H.; Hallstrom, T. C.; Tunyaplin, C.; Calame, K. and Nevins, J. R. (2003): Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor, Mol Cell Biol, (vol. 23), No. 11, pp.3707-20. [135] Giangrande, P. H.; Zhu, W.; Rempel, R. E.; Laakso, N. and Nevins, J. R. (2004): Combinatorial gene control involving E2F and E Box family members, Embo J, (vol. 23), No. 6, pp.1336-47. [136] Cloud, J. E.; Rogers, C.; Reza, T. L.; Ziebold, U.; Stone, J. R.; Picard, M. H.; Caron, A. M.; Bronson, R. T. and Lees, J. A. (2002): Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo, Mol Cell Biol, (vol. 22), No. 8, pp.2663-72. [137] Lu, K. H.; Patterson, A. P.; Wang, L.; Marquez, R. T.; Atkinson, E. N.; Baggerly, K. A.; Ramoth, L. R.; Rosen, D. G.; Liu, J.; Hellstrom, I.; Smith, D.; Hartmann, L.; Fishman, D.; Berchuck, A.; Schmandt, R.; Whitaker, R.; Gershenson, D. M.; Mills, G. B. and Bast, R. C., Jr. (2004): Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis, Clin Cancer Res, (vol. 10), No. 10, pp.3291-300. [138] Cooper, C. S.; Nicholson, A. G.; Foster, C.; Dodson, A.; Edwards, S.; Fletcher, A.; Roe, T.; Clark, J.; Joshi, A.; Norman, A.; Feber, A.; Lin, D.; Gao, Y.; Shipley, J. and Cheng, S. J. (2006): Nuclear overexpression of the E2F3 transcription factor in human lung cancer, Lung Cancer, (vol. 54), No. 2, pp.155-62. [139] Foster, C. S.; Falconer, A.; Dodson, A. R.; Norman, A. R.; Dennis, N.; Fletcher, A.; Southgate, C.; Dowe, A.; Dearnaley, D.; Jhavar, S.; Eeles, R.; Feber, A. and Cooper, C. S. (2004): Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome, Oncogene, (vol. 23), No. 35, pp.5871-9. [140] Feber, A.; Clark, J.; Goodwin, G.; Dodson, A. R.; Smith, P. H.; Fletcher, A.; Edwards, S.; Flohr, P.; Falconer, A.; Roe, T.; Kovacs, G.; Dennis, N.; Fisher, C.; Wooster, R.; Huddart, R.; Foster, C. S. and Cooper, C. S. (2004): Amplification and overexpression of E2F3 in human bladder cancer, Oncogene, (vol. 23), No. 8, pp.1627-30. [141] Oeggerli, M.; Tomovska, S.; Schraml, P.; Calvano-Forte, D.; Schafroth, S.; Simon, R.; Gasser, T.; Mihatsch, M. J. and Sauter, G. (2004): E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer, Oncogene, (vol. 23), No. 33, pp.5616-23. [142] Orlic, M.; Spencer, C. E.; Wang, L. and Gallie, B. L. (2006): Expression analysis of 6p22 genomic gain in retinoblastoma, Genes Chromosomes Cancer, (vol. 45), No. 1, pp.72-82. [143] Olsson, A. Y.; Feber, A.; Edwards, S.; Te Poele, R.; Giddings, I.; Merson, S. and Cooper, C. S. (2007): Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells, Oncogene, (vol. 26), No. 7, pp.1028-37. [144] Hurst, C. D.; Tomlinson, D. C.; Williams, S. V.; Platt, F. M. and Knowles, M. A. (2007): Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification, Oncogene. [145] Chang, C.; Simmons, D. T.; Martin, M. A. and Mora, P. T. (1979): Identification and partial characterization of new antigens from simian virus 40-transformed mouse cells, J Virol, (vol. 31), No. 2, pp.463-71. [146] Kress, M.; May, E.; Cassingena, R. and May, P. (1979): Simian virus 40-transformed cells express new species of proteins precipitable by anti-simian virus 40 tumor serum, J Virol, (vol. 31), No. 2, pp.472-83. [147] Lane, D. P. and Crawford, L. V. (1979): T antigen is bound to a host protein in SV40-transformed cells, Nature, (vol. 278), No. 5701, pp.261-3. [148] Linzer, D. I. and Levine, A. J. (1979): Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells, Cell, (vol. 17), No. 1, pp.43-52. [149] Hinds, P.; Finlay, C. and Levine, A. J. (1989): Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation, J Virol, (vol. 63), No. 2, pp.739-46. [150] Soussi, T. and Lozano, G. (2005): p53 mutation heterogeneity in cancer, Biochem Biophys Res Commun, (vol. 331), No. 3, pp.834-42. [151] Malkin, D.; Li, F. P.; Strong, L. C.; Fraumeni, J. F., Jr.; Nelson, C. E.; Kim, D. H.; Kassel, J.; Gryka, M. A.; Bischoff, F. Z.; Tainsky, M. A. and et al. (1990): Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms, Science, (vol. 250), No. 4985, pp.1233-8. [152] Srivastava, S.; Zou, Z. Q.; Pirollo, K.; Blattner, W. and Chang, E. H. (1990): Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome, Nature, (vol. 348), No. 6303, pp.747-9. [153] Royds, J. A. and Iacopetta, B. (2006): p53 and disease: when the guardian angel fails, Cell Death Differ, (vol. 13), No. 6, pp.1017-26. [154] Donehower, L. A.; Harvey, M.; Slagle, B. L.; McArthur, M. J.; Montgomery, C. A., Jr.; Butel, J. S. and Bradley, A. (1992): Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours, Nature, (vol. 356), No. 6366, pp.215-21. [155] Harris, S. L. and Levine, A. J. (2005): The p53 pathway: positive and negative feedback loops, Oncogene, (vol. 24), No. 17, pp.2899-908. [156] Kubbutat, M. H.; Jones, S. N. and Vousden, K. H. (1997): Regulation of p53 stability by Mdm2, Nature, (vol. 387), No. 6630, pp.299-303. [157] Chehab, N. H.; Malikzay, A.; Appel, M. and Halazonetis, T. D. (2000): Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53, Genes Dev, (vol. 14), No. 3, pp.278-88. [158] Shieh, S. Y.; Ahn, J.; Tamai, K.; Taya, Y. and Prives, C. (2000): The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites, Genes Dev, (vol. 14), No. 3, pp.289-300. [159] Liu, Q.; Guntuku, S.; Cui, X. S.; Matsuoka, S.; Cortez, D.; Tamai, K.; Luo, G.; Carattini-Rivera, S.; DeMayo, F.; Bradley, A.; Donehower, L. A. and Elledge, S. J. (2000): Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint, Genes Dev, (vol. 14), No. 12, pp.1448-59. [160] Barak, Y. and Oren, M. (1992): Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest, Embo J, (vol. 11), No. 6, pp.2115-21. [161] Zhang, Y.; Xiong, Y. and Yarbrough, W. G. (1998): ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways, Cell, (vol. 92), No. 6, pp.725-34. [162] Kamijo, T.; Weber, J. D.; Zambetti, G.; Zindy, F.; Roussel, M. F. and Sherr, C. J. (1998): Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2, Proc Natl Acad Sci U S A, (vol. 95), No. 14, pp.8292-7. [163] Robertson, K. D. and Jones, P. A. (1998): The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53, Mol Cell Biol, (vol. 18), No. 11, pp.6457-73. [164] Honda, R. and Yasuda, H. (1999): Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53, Embo J, (vol. 18), No. 1, pp.22-7. [165] Russell, J. L.; Powers, J. T.; Rounbehler, R. J.; Rogers, P. M.; Conti, C. J. and Johnson, D. G. (2002): ARF differentially modulates apoptosis induced by E2F1 and Myc, Mol Cell Biol, (vol. 22), No. 5, pp.1360-8. [166] Lane, D. P. (1992): Cancer. p53, guardian of the genome, Nature, (vol. 358), No. 6381, pp.15-6. [167] Vousden, K. H. (2006): Outcomes of p53 activation--spoilt for choice, J Cell Sci, (vol. 119), No. Pt 24, pp.5015-20. [168] el-Deiry, W. S.; Tokino, T.; Velculescu, V. E.; Levy, D. B.; Parsons, R.; Trent, J. M.; Lin, D.; Mercer, W. E.; Kinzler, K. W. and Vogelstein, B. (1993): WAF1, a potential mediator of p53 tumor suppression, Cell, (vol. 75), No. 4, pp.817-25. [169] Wu, X.; Bayle, J. H.; Olson, D. and Levine, A. J. (1993): The p53-mdm-2 autoregulatory feedback loop, Genes Dev, (vol. 7), No. 7A, pp.1126-32. [170] Miyashita, T. and Reed, J. C. (1995): Tumor suppressor p53 is a direct transcriptional activator of the human bax gene, Cell, (vol. 80), No. 2, pp.293-9. [171] Hermeking, H.; Lengauer, C.; Polyak, K.; He, T. C.; Zhang, L.; Thiagalingam, S.; Kinzler, K. W. and Vogelstein, B. (1997): 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression, Mol Cell, (vol. 1), No. 1, pp.3-11. [172] Oda, E.; Ohki, R.; Murasawa, H.; Nemoto, J.; Shibue, T.; Yamashita, T.; Tokino, T.; Taniguchi, T. and Tanaka, N. (2000): Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis, Science, (vol. 288), No. 5468, pp.1053-8. [173] Nakano, K. and Vousden, K. H. (2001): PUMA, a novel proapoptotic gene, is induced by p53, Mol Cell, (vol. 7), No. 3, pp.683-94. [174] Wu, W. S.; Heinrichs, S.; Xu, D.; Garrison, S. P.; Zambetti, G. P.; Adams, J. M. and Look, A. T. (2005): Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma, Cell, (vol. 123), No. 4, pp.641-53. [175] Bensaad, K.; Tsuruta, A.; Selak, M. A.; Vidal, M. N.; Nakano, K.; Bartrons, R.; Gottlieb, E. and Vousden, K. H. (2006): TIGAR, a p53-inducible regulator of glycolysis and apoptosis, Cell, (vol. 126), No. 1, pp.107-20. [176] Kuerbitz, S. J.; Plunkett, B. S.; Walsh, W. V. and Kastan, M. B. (1992): Wild-type p53 is a cell cycle checkpoint determinant following irradiation, Proc Natl Acad Sci U S A, (vol. 89), No. 16, pp.7491-5. [177] Taylor, W. R. and Stark, G. R. (2001): Regulation of the G2/M transition by p53, Oncogene, (vol. 20), No. 15, pp.1803-15. [178] Iliakis, G.; Wang, Y.; Guan, J. and Wang, H. (2003): DNA damage checkpoint control in cells exposed to ionizing radiation, Oncogene, (vol. 22), No. 37, pp.5834-47. [179] Brown, J. P.; Wei, W. and Sedivy, J. M. (1997): Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts, Science, (vol. 277), No. 5327, pp.831-4. [180] Brugarolas, J.; Chandrasekaran, C.; Gordon, J. I.; Beach, D.; Jacks, T. and Hannon, G. J. (1995): Radiation-induced cell cycle arrest compromised by p21 deficiency, Nature, (vol. 377), No. 6549, pp.552-7. [181] Deng, C.; Zhang, P.; Harper, J. W.; Elledge, S. J. and Leder, P. (1995): Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control, Cell, (vol. 82), No. 4, pp.675-84. [182] Pantoja, C. and Serrano, M. (1999): Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras, Oncogene, (vol. 18), No. 35, pp.4974-82. [183] Harvey, M.; Sands, A. T.; Weiss, R. S.; Hegi, M. E.; Wiseman, R. W.; Pantazis, P.; Giovanella, B. C.; Tainsky, M. A.; Bradley, A. and Donehower, L. A. (1993): In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice, Oncogene, (vol. 8), No. 9, pp.2457-67. [184] Kortlever, R. M.; Higgins, P. J. and Bernards, R. (2006): Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence, Nat Cell Biol, (vol. 8), No. 8, pp.877-84. [185] Cordenonsi, M.; Dupont, S.; Maretto, S.; Insinga, A.; Imbriano, C. and Piccolo, S. (2003): Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads, Cell, (vol. 113), No. 3, pp.301-14. [186] Cordenonsi, M.; Montagner, M.; Adorno, M.; Zacchigna, L.; Martello, G.; Mamidi, A.; Soligo, S.; Dupont, S. and Piccolo, S. (2007): Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation, Science, (vol. 315), No. 5813, pp.840-3. [187] Roberts, A. B and M.B., Sporn (1990): The transforming growth factors-betas., In: Sporn MB, Roberts AB, editors. Peptide growth factors and their receptors, Part I, Vol 95. Berlin: Springer-Verlag, pp.419-472. [188] Lawrence, D. A. (1991): Identification and activation of latent transforming growth factor beta, Methods Enzymol, (vol. 198), pp.327-36. [189] Gleizes, P. E.; Munger, J. S.; Nunes, I.; Harpel, J. G.; Mazzieri, R.; Noguera, I. and Rifkin, D. B. (1997): TGF-beta latency: biological significance and mechanisms of activation, Stem Cells, (vol. 15), No. 3, pp.190-7. [190] Lutz, M. and Knaus, P. (2002): Integration of the TGF-beta pathway into the cellular signalling network, Cell Signal, (vol. 14), No. 12, pp.977-88. [191] Massague, J. (2000): How cells read TGF-beta signals, Nat Rev Mol Cell Biol, (vol. 1), No. 3, pp.169-78. [192] Goumans, M. J.; Valdimarsdottir, G.; Itoh, S.; Lebrin, F.; Larsson, J.; Mummery, C.; Karlsson, S. and ten Dijke, P. (2003): Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling, Mol Cell, (vol. 12), No. 4, pp.817-28. [193] Tsukazaki, T.; Chiang, T. A.; Davison, A. F.; Attisano, L. and Wrana, J. L. (1998): SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor, Cell, (vol. 95), No. 6, pp.779-91. [194] Dennler, S.; Itoh, S.; Vivien, D.; ten Dijke, P.; Huet, S. and Gauthier, J. M. (1998): Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene, Embo J, (vol. 17), No. 11, pp.3091-100. [195] Zhou, S.; Zawel, L.; Lengauer, C.; Kinzler, K. W. and Vogelstein, B. (1998): Characterization of human FAST-1, a TGF beta and activin signal transducer, Mol Cell, (vol. 2), No. 1, pp.121-7. [196] Hua, X.; Liu, X.; Ansari, D. O. and Lodish, H. F. (1998): Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene, Genes Dev, (vol. 12), No. 19, pp.3084-95. [197] Janknecht, R.; Wells, N. J. and Hunter, T. (1998): TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300, Genes Dev, (vol. 12), No. 14, pp.2114-9. [198] Liberati, N. T.; Datto, M. B.; Frederick, J. P.; Shen, X.; Wong, C.; Rougier-Chapman, E. M. and Wang, X. F. (1999): Smads bind directly to the Jun family of AP-1 transcription factors, Proc Natl Acad Sci U S A, (vol. 96), No. 9, pp.4844-9. [199] Labbe, E.; Letamendia, A. and Attisano, L. (2000): Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways, Proc Natl Acad Sci U S A, (vol. 97), No. 15, pp.8358-63. [200] Gomis, R. R.; Alarcon, C.; Nadal, C.; Van Poznak, C. and Massague, J. (2006): C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells, Cancer Cell, (vol. 10), No. 3, pp.203-14. [201] Stroschein, S. L.; Wang, W.; Zhou, S.; Zhou, Q. and Luo, K. (1999): Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein, Science, (vol. 286), No. 5440, pp.771-4. [202] Wotton, D.; Lo, R. S.; Lee, S. and Massague, J. (1999): A Smad transcriptional corepressor, Cell, (vol. 97), No. 1, pp.29-39. [203] Luo, K.; Stroschein, S. L.; Wang, W.; Chen, D.; Martens, E.; Zhou, S. and Zhou, Q. (1999): The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling, Genes Dev, (vol. 13), No. 17, pp.2196-206. [204] Di Guglielmo, G. M.; Le Roy, C.; Goodfellow, A. F. and Wrana, J. L. (2003): Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover, Nat Cell Biol, (vol. 5), No. 5, pp.410-21. [205] Inman, G. J.; Nicolas, F. J. and Hill, C. S. (2002): Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity, Mol Cell, (vol. 10), No. 2, pp.283-94. [206] Derynck, R. and Zhang, Y. E. (2003): Smad-dependent and Smad-independent pathways in TGF-beta family signalling, Nature, (vol. 425), No. 6958, pp.577-84. [207] Siegel, P. M. and Massague, J. (2003): Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer, Nat Rev Cancer, (vol. 3), No. 11, pp.807-21. [208] Kang, Y. (2006): Pro-metastasis function of TGFbeta mediated by the Smad pathway, J Cell Biochem, (vol. 98), No. 6, pp.1380-90. [209] Sorrentino, V. and Bandyopadhyay, S. (1989): TGF beta inhibits Go/S-phase transition in primary fibroblasts. Loss of response to the antigrowth effect of TGF beta is observed after immortalization, Oncogene, (vol. 4), No. 5, pp.569-74. [210] Sudarshan, C.; Yaswen, L.; Kulkarni, A. and Raghow, R. (1998): Phenotypic consequences of transforming growth factor beta1 gene ablation in murine embryonic fibroblasts: autocrine control of cell proliferation and extracellular matrix biosynthesis, J Cell Physiol, (vol. 176), No. 1, pp.67-75. [211] Piek, E.; Ju, W. J.; Heyer, J.; Escalante-Alcalde, D.; Stewart, C. L.; Weinstein, M.; Deng, C.; Kucherlapati, R.; Bottinger, E. P. and Roberts, A. B. (2001): Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts, J Biol Chem, (vol. 276), No. 23, pp.19945-53. [212] Karlsson, G.; Liu, Y.; Larsson, J.; Goumans, M. J.; Lee, J. S.; Thorgeirsson, S. S.; Ringner, M. and Karlsson, S. (2005): Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling, Physiol Genomics, (vol. 21), No. 3, pp.396-403. [213] Hocevar, B. A.; Brown, T. L. and Howe, P. H. (1999): TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway, Embo J, (vol. 18), No. 5, pp.1345-56. [214] Herrera, R. E.; Makela, T. P. and Weinberg, R. A. (1996): TGF beta-induced growth inhibition in primary fibroblasts requires the retinoblastoma protein, Mol Biol Cell, (vol. 7), No. 9, pp.1335-42. [215] Laiho, M.; DeCaprio, J. A.; Ludlow, J. W.; Livingston, D. M. and Massague, J. (1990): Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation, Cell, (vol. 62), No. 1, pp.175-85. [216] Chen, C. R.; Kang, Y.; Siegel, P. M. and Massague, J. (2002): E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression, Cell, (vol. 110), No. 1, pp.19-32. [217] Kang, Y.; Chen, C. R. and Massague, J. (2003): A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells, Mol Cell, (vol. 11), No. 4, pp.915-26. [218] Seoane, J.; Pouponnot, C.; Staller, P.; Schader, M.; Eilers, M. and Massague, J. (2001): TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b, Nat Cell Biol, (vol. 3), No. 4, pp.400-8. [219] Seoane, J.; Le, H. V.; Shen, L.; Anderson, S. A. and Massague, J. (2004): Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation, Cell, (vol. 117), No. 2, pp.211-23. [220] Gomis, R. R.; Alarcon, C.; He, W.; Wang, Q.; Seoane, J.; Lash, A. and Massague, J. (2006): A FoxO-Smad synexpression group in human keratinocytes, Proc Natl Acad Sci U S A, (vol. 103), No. 34, pp.12747-52. [221] Vijayachandra, K.; Lee, J. and Glick, A. B. (2003): Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model, Cancer Res, (vol. 63), No. 13, pp.3447-52. [222] Zhang, H. and Cohen, S. N. (2004): Smurf2 up-regulation activates telomere-dependent senescence, Genes Dev, (vol. 18), No. 24, pp.3028-40. [223] Glick, A. B.; Lee, M. M.; Darwiche, N.; Kulkarni, A. B.; Karlsson, S. and Yuspa, S. H. (1994): Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma, Genes Dev, (vol. 8), No. 20, pp.2429-40. [224] Tremain, R.; Marko, M.; Kinnimulki, V.; Ueno, H.; Bottinger, E. and Glick, A. (2000): Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras, Oncogene, (vol. 19), No. 13, pp.1698-709. [225] Lin, H. K.; Bergmann, S. and Pandolfi, P. P. (2004): Cytoplasmic PML function in TGF-beta signalling, Nature, (vol. 431), No. 7005, pp.205-11. [226] de Stanchina, E.; Querido, E.; Narita, M.; Davuluri, R. V.; Pandolfi, P. P.; Ferbeyre, G. and Lowe, S. W. (2004): PML is a direct p53 target that modulates p53 effector functions, Mol Cell, (vol. 13), No. 4, pp.523-35. [227] De Petro, G.; Copeta, A. and Barlati, S. (1994): Urokinase-type and tissue-type plasminogen activators as growth factors of human fibroblasts, Exp Cell Res, (vol. 213), No. 1, pp.286-94. [228] Tachibana, I.; Imoto, M.; Adjei, P. N.; Gores, G. J.; Subramaniam, M.; Spelsberg, T. C. and Urrutia, R. (1997): Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells, J Clin Invest, (vol. 99), No. 10, pp.2365-74. [229] Jang, C. W.; Chen, C. H.; Chen, C. C.; Chen, J. Y.; Su, Y. H. and Chen, R. H. (2002): TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase, Nat Cell Biol, (vol. 4), No. 1, pp.51-8. [230] Valderrama-Carvajal, H.; Cocolakis, E.; Lacerte, A.; Lee, E. H.; Krystal, G.; Ali, S. and Lebrun, J. J. (2002): Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP, Nat Cell Biol, (vol. 4), No. 12, pp.963-9. [231] Zhang, S.; Ekman, M.; Thakur, N.; Bu, S.; Davoodpour, P.; Grimsby, S.; Tagami, S.; Heldin, C. H. and Landstrom, M. (2006): TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner, Cell Cycle, (vol. 5), No. 23, pp.2787-95. [232] Schuster, N. and Krieglstein, K. (2002): Mechanisms of TGF-beta-mediated apoptosis, Cell Tissue Res, (vol. 307), No. 1, pp.1-14. [233] Thiery, J. P. and Sleeman, J. P. (2006): Complex networks orchestrate epithelial-mesenchymal transitions, Nat Rev Mol Cell Biol, (vol. 7), No. 2, pp.131-42. [234] Derynck, R. and Akhurst, R. J. (2007): Differentiation plasticity regulated by TGF-beta family proteins in development and disease, Nat Cell Biol, (vol. 9), No. 9, pp.1000-4. [235] Savagner, P.; Yamada, K. M. and Thiery, J. P. (1997): The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition, J Cell Biol, (vol. 137), No. 6, pp.1403-19. [236] Guaita, S.; Puig, I.; Franci, C.; Garrido, M.; Dominguez, D.; Batlle, E.; Sancho, E.; Dedhar, S.; De Herreros, A. G. and Baulida, J. (2002): Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression, J Biol Chem, (vol. 277), No. 42, pp.39209-16. [237] Ohkubo, T. and Ozawa, M. (2004): The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation, J Cell Sci, (vol. 117), No. Pt 9, pp.1675-85. [238] Bolos, V.; Peinado, H.; Perez-Moreno, M. A.; Fraga, M. F.; Esteller, M. and Cano, A. (2003): The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors, J Cell Sci, (vol. 116), No. Pt 3, pp.499-511. [239] Mani, S. A.; Yang, J.; Brooks, M.; Schwaninger, G.; Zhou, A.; Miura, N.; Kutok, J. L.; Hartwell, K.; Richardson, A. L. and Weinberg, R. A. (2007): Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers, Proc Natl Acad Sci U S A, (vol. 104), No. 24, pp.10069-74. [240] Bindels, S.; Mestdagt, M.; Vandewalle, C.; Jacobs, N.; Volders, L.; Noel, A.; van Roy, F.; Berx, G.; Foidart, J. M. and Gilles, C. (2006): Regulation of vimentin by SIP1 in human epithelial breast tumor cells, Oncogene, (vol. 25), No. 36, pp.4975-85. [241] Zavadil, J. and Bottinger, E. P. (2005): TGF-beta and epithelial-to-mesenchymal transitions, Oncogene, (vol. 24), No. 37, pp.5764-74. [242] Dickson, M. C.; Martin, J. S.; Cousins, F. M.; Kulkarni, A. B.; Karlsson, S. and Akhurst, R. J. (1995): Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice, Development, (vol. 121), No. 6, pp.1845-54. [243] Oshima, M.; Oshima, H. and Taketo, M. M. (1996): TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis, Dev Biol, (vol. 179), No. 1, pp.297-302. [244] Larsson, J.; Goumans, M. J.; Sjostrand, L. J.; van Rooijen, M. A.; Ward, D.; Leveen, P.; Xu, X.; ten Dijke, P.; Mummery, C. L. and Karlsson, S. (2001): Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice, Embo J, (vol. 20), No. 7, pp.1663-73. [245] Shull, M. M.; Ormsby, I.; Kier, A. B.; Pawlowski, S.; Diebold, R. J.; Yin, M.; Allen, R.; Sidman, C.; Proetzel, G.; Calvin, D. and et al. (1992): Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease, Nature, (vol. 359), No. 6397, pp.693-9. [246] Diebold, R. J.; Eis, M. J.; Yin, M.; Ormsby, I.; Boivin, G. P.; Darrow, B. J.; Saffitz, J. E. and Doetschman, T. (1995): Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated, Proc Natl Acad Sci U S A, (vol. 92), No. 26, pp.12215-9. [247] Crowe, M. J.; Doetschman, T. and Greenhalgh, D. G. (2000): Delayed wound healing in immunodeficient TGF-beta 1 knockout mice, J Invest Dermatol, (vol. 115), No. 1, pp.3-11. [248] Datto, M. B.; Frederick, J. P.; Pan, L.; Borton, A. J.; Zhuang, Y. and Wang, X. F. (1999): Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction, Mol Cell Biol, (vol. 19), No. 4, pp.2495-504. [249] Yang, X.; Letterio, J. J.; Lechleider, R. J.; Chen, L.; Hayman, R.; Gu, H.; Roberts, A. B. and Deng, C. (1999): Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta, Embo J, (vol. 18), No. 5, pp.1280-91. [250] Zhu, Y.; Richardson, J. A.; Parada, L. F. and Graff, J. M. (1998): Smad3 mutant mice develop metastatic colorectal cancer, Cell, (vol. 94), No. 6, pp.703-14. [251] Waldrip, W. R.; Bikoff, E. K.; Hoodless, P. A.; Wrana, J. L. and Robertson, E. J. (1998): Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo, Cell, (vol. 92), No. 6, pp.797-808. [252] Weinstein, M.; Yang, X.; Li, C.; Xu, X.; Gotay, J. and Deng, C. X. (1998): Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2, Proc Natl Acad Sci U S A, (vol. 95), No. 16, pp.9378-83. [253] Nomura, M. and Li, E. (1998): Smad2 role in mesoderm formation, left-right patterning and craniofacial development, Nature, (vol. 393), No. 6687, pp.786-90. [254] Yang, X.; Li, C.; Xu, X. and Deng, C. (1998): The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice, Proc Natl Acad Sci U S A, (vol. 95), No. 7, pp.3667-72. [255] Sirard, C.; Kim, S.; Mirtsos, C.; Tadich, P.; Hoodless, P. A.; Itie, A.; Maxson, R.; Wrana, J. L. and Mak, T. W. (2000): Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling, J Biol Chem, (vol. 275), No. 3, pp.2063-70. [256] Takaku, K.; Miyoshi, H.; Matsunaga, A.; Oshima, M.; Sasaki, N. and Taketo, M. M. (1999): Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice, Cancer Res, (vol. 59), No. 24, pp.6113-7. [257] Chen, C. R.; Kang, Y. and Massague, J. (2001): Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program, Proc Natl Acad Sci U S A, (vol. 98), No. 3, pp.992-9. [258] Levy, L. and Hill, C. S. (2006): Alterations in components of the TGF-beta superfamily signaling pathways in human cancer, Cytokine Growth Factor Rev, (vol. 17), No. 1-2, pp.41-58. [259] O'Brien, C. (1996): New tumor suppressor found in pancreatic cancer, Science, (vol. 271), No. 5247, p.294. [260] Takagi, Y.; Kohmura, H.; Futamura, M.; Kida, H.; Tanemura, H.; Shimokawa, K. and Saji, S. (1996): Somatic alterations of the DPC4 gene in human colorectal cancers in vivo, Gastroenterology, (vol. 111), No. 5, pp.1369-72. [261] Wikstrom, P.; Stattin, P.; Franck-Lissbrant, I.; Damber, J. E. and Bergh, A. (1998): Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer, Prostate, (vol. 37), No. 1, pp.19-29. [262] Pasche, B. (2001): Role of transforming growth factor beta in cancer, J Cell Physiol, (vol. 186), No. 2, pp.153-68. [263] Bierie, B. and Moses, H. L. (2006): TGF-beta and cancer, Cytokine Growth Factor Rev, (vol. 17), No. 1-2, pp.29-40. [264] Pierce, D. F., Jr.; Gorska, A. E.; Chytil, A.; Meise, K. S.; Page, D. L.; Coffey, R. J., Jr. and Moses, H. L. (1995): Mammary tumor suppression by transforming growth factor beta 1 transgene expression, Proc Natl Acad Sci U S A, (vol. 92), No. 10, pp.4254-8. [265] Muraoka, R. S.; Koh, Y.; Roebuck, L. R.; Sanders, M. E.; Brantley-Sieders, D.; Gorska, A. E.; Moses, H. L. and Arteaga, C. L. (2003): Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1, Mol Cell Biol, (vol. 23), No. 23, pp.8691-703. [266] Siegel, P. M.; Shu, W.; Cardiff, R. D.; Muller, W. J. and Massague, J. (2003): Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis, Proc Natl Acad Sci U S A, (vol. 100), No. 14, pp.8430-5. [267] Bhowmick, N. A.; Chytil, A.; Plieth, D.; Gorska, A. E.; Dumont, N.; Shappell, S.; Washington, M. K.; Neilson, E. G. and Moses, H. L. (2004): TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia, Science, (vol. 303), No. 5659, pp.848-51. [268] Cheng, N.; Bhowmick, N. A.; Chytil, A.; Gorksa, A. E.; Brown, K. A.; Muraoka, R.; Arteaga, C. L.; Neilson, E. G.; Hayward, S. W. and Moses, H. L. (2005): Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks, Oncogene, (vol. 24), No. 32, pp.5053-68. [269] Liu, F (2006): Delineating the TGF-beta/SMAD-induced cytostatic response, P. ten Dijke and C.-H. Heldin (eds.), Smad Signal Transduction, Springer, pp.75-91. [270] Thatikunta, P.; Raj, G. V.; Kundu, M.; Khalili, K. and Amini, S. (1997): The transcription factor E2F-1 modulates TGF-beta1 RNA expression in glial cells, Oncogene, (vol. 14), No. 24, pp.2959-69. [271] Jordan-Sciutto, K. L.; Logan, T. J.; Norton, P. A.; Derfoul, A.; Dodge, G. R. and Hall, D. J. (1997): Reduction in fibronectin expression and alteration in cell morphology are coincident in NIH3T3 cells expressing a mutant E2F1 transcription factor, Exp Cell Res, (vol. 236), No. 2, pp.527-36. [272] Hiyama, H.; Iavarone, A. and Reeves, S. A. (1998): Regulation of the cdk inhibitor p21 gene during cell cycle progression is under the control of the transcription factor E2F, Oncogene, (vol. 16), No. 12, pp.1513-23. [273] Koziczak, M.; Krek, W. and Nagamine, Y. (2000): Pocket protein-independent repression of urokinase-type plasminogen activator and plasminogen activator inhibitor 1 gene expression by E2F1, Mol Cell Biol, (vol. 20), No. 6, pp.2014-22. [274] Hu, X.; Cress, W. D.; Zhong, Q. and Zuckerman, K. S. (2000): Transforming growth factor beta inhibits the phosphorylation of pRB at multiple serine/threonine sites and differentially regulates the formation of pRB family-E2F complexes in human myeloid leukemia cells, Biochem Biophys Res Commun, (vol. 276), No. 3, pp.930-9. [275] Mu, X. C. and Higgins, P. J. (1995): Differential growth state-dependent regulation of plasminogen activator inhibitor type-1 expression in senescent IMR-90 human diploid fibroblasts, J Cell Physiol, (vol. 165), No. 3, pp.647-57. [276] Zindy, F.; Eischen, C. M.; Randle, D. H.; Kamijo, T.; Cleveland, J. L.; Sherr, C. J. and Roussel, M. F. (1998): Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization, Genes Dev, (vol. 12), No. 15, pp.2424-33. [277] Nishio, K. and Inoue, A. (2005): Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts, Histochem Cell Biol, (vol. 123), No. 3, pp.263-73. [278] Koopman, G.; Reutelingsperger, C. P.; Kuijten, G. A.; Keehnen, R. M.; Pals, S. T. and van Oers, M. H. (1994): Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis, Blood, (vol. 84), No. 5, pp.1415-20. [279] Vogelstein, B.; Lane, D. and Levine, A. J. (2000): Surfing the p53 network, Nature, (vol. 408), No. 6810, pp.307-10. [280] el-Deiry, W. S.; Harper, J. W.; O'Connor, P. M.; Velculescu, V. E.; Canman, C. E.; Jackman, J.; Pietenpol, J. A.; Burrell, M.; Hill, D. E.; Wang, Y. and et al. (1994): WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis, Cancer Res, (vol. 54), No. 5, pp.1169-74. [281] Iaquinta, P. J.; Aslanian, A. and Lees, J. A. (2005): Regulation of the Arf/p53 tumor surveillance network by E2F, Cold Spring Harb Symp Quant Biol, (vol. 70), pp.309-16. [282] Datto, M. B.; Li, Y.; Panus, J. F.; Howe, D. J.; Xiong, Y. and Wang, X. F. (1995): Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism, Proc Natl Acad Sci U S A, (vol. 92), No. 12, pp.5545-9. [283] Kasai, H.; Allen, J. T.; Mason, R. M.; Kamimura, T. and Zhang, Z. (2005): TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT), Respir Res, (vol. 6), p.56. [284] Illman, S. A.; Lehti, K.; Keski-Oja, J. and Lohi, J. (2006): Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells, J Cell Sci, (vol. 119), No. Pt 18, pp.3856-65. [285] Narumiya, S. and Yasuda, S. (2006): Rho GTPases in animal cell mitosis, Curr Opin Cell Biol, (vol. 18), No. 2, pp.199-205. [286] Yuce, O.; Piekny, A. and Glotzer, M. (2005): An ECT2-centralspindlin complex regulates the localization and function of RhoA, J Cell Biol, (vol. 170), No. 4, pp.571-82. [287] Oceguera-Yanez, F.; Kimura, K.; Yasuda, S.; Higashida, C.; Kitamura, T.; Hiraoka, Y.; Haraguchi, T. and Narumiya, S. (2005): Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis, J Cell Biol, (vol. 168), No. 2, pp.221-32. [288] Ban, R.; Irino, Y.; Fukami, K. and Tanaka, H. (2004): Human mitotic spindle-associated protein PRC1 inhibits MgcRacGAP activity toward Cdc42 during the metaphase, J Biol Chem, (vol. 279), No. 16, pp.16394-402. [289] Zhao, W. M.; Seki, A. and Fang, G. (2006): Cep55, a microtubule-bundling protein, associates with centralspindlin to control the midbody integrity and cell abscission during cytokinesis, Mol Biol Cell, (vol. 17), No. 9, pp.3881-96. [290] Sotillo, R.; Hernando, E.; Diaz-Rodriguez, E.; Teruya-Feldstein, J.; Cordon-Cardo, C.; Lowe, S. W. and Benezra, R. (2007): Mad2 overexpression promotes aneuploidy and tumorigenesis in mice, Cancer Cell, (vol. 11), No. 1, pp.9-23. [291] Hirose, K.; Kawashima, T.; Iwamoto, I.; Nosaka, T. and Kitamura, T. (2001): MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody, J Biol Chem, (vol. 276), No. 8, pp.5821-8. [292] Zhao, W. M. and Fang, G. (2005): MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis, Proc Natl Acad Sci U S A, (vol. 102), No. 37, pp.13158-63. [293] Inman, G. J.; Nicolas, F. J.; Callahan, J. F.; Harling, J. D.; Gaster, L. M.; Reith, A. D.; Laping, N. J. and Hill, C. S. (2002): SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7, Mol Pharmacol, (vol. 62), No. 1, pp.65-74. [294] Laping, N. J.; Grygielko, E.; Mathur, A.; Butter, S.; Bomberger, J.; Tweed, C.; Martin, W.; Fornwald, J.; Lehr, R.; Harling, J.; Gaster, L.; Callahan, J. F. and Olson, B. A. (2002): Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542, Mol Pharmacol, (vol. 62), No. 1, pp.58-64. [295] Harvey, D. M. and Levine, A. J. (1991): p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts, Genes Dev, (vol. 5), No. 12B, pp.2375-85. [296] MacLaren, A.; Black, E. J.; Clark, W. and Gillespie, D. A. (2004): c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation, Mol Cell Biol, (vol. 24), No. 20, pp.9006-18. [297] Dimri, G. P.; Itahana, K.; Acosta, M. and Campisi, J. (2000): Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor, Mol Cell Biol, (vol. 20), No. 1, pp.273-85. [298] Miki, J.; Fujimura, Y.; Koseki, H. and Kamijo, T. (2007): Polycomb complexes regulate cellular senescence by repression of ARF in cooperation with E2F3, Genes Cells, (vol. 12), No. 12, pp.1371-82. [299] Lazzerini Denchi, E.; Attwooll, C.; Pasini, D. and Helin, K. (2005): Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland, Mol Cell Biol, (vol. 25), No. 7, pp.2660-72. [300] Kang, D. H.; Hong, Y. S.; Lim, H. J.; Choi, J. H.; Han, D. S. and Yoon, K. I. (1999): High glucose solution and spent dialysate stimulate the synthesis of transforming growth factor-beta1 of human peritoneal mesothelial cells: effect of cytokine costimulation, Perit Dial Int, (vol. 19), No. 3, pp.221-30. [301] Daniels, M. C.; McClain, D. A. and Crook, E. D. (2000): Transcriptional regulation of transforming growth factor beta1 by glucose: investigation into the role of the hexosamine biosynthesis pathway, Am J Med Sci, (vol. 319), No. 3, pp.138-42. [302] Koziczak, M.; Muller, H.; Helin, K. and Nagamine, Y. (2001): E2F1-mediated transcriptional inhibition of the plasminogen activator inhibitor type 1 gene, Eur J Biochem, (vol. 268), No. 18, pp.4969-78. [303] Hua, X.; Miller, Z. A.; Wu, G.; Shi, Y. and Lodish, H. F. (1999): Specificity in transforming growth factor beta-induced transcription of the plasminogen activator inhibitor-1 gene: interactions of promoter DNA, transcription factor muE3, and Smad proteins, Proc Natl Acad Sci U S A, (vol. 96), No. 23, pp.13130-5. [304] de Bruin, A.; Wu, L.; Saavedra, H. I.; Wilson, P.; Yang, Y.; Rosol, T. J.; Weinstein, M.; Robinson, M. L. and Leone, G. (2003): Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice, Proc Natl Acad Sci U S A, (vol. 100), No. 11, pp.6546-51. [305] Parisi, T.; Yuan, T. L.; Faust, A. M.; Caron, A. M.; Bronson, R. and Lees, J. A. (2007): Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues, Mol Cell Biol, (vol. 27), No. 6, pp.2283-93. [306] Goldin, G. V. and Opperman, L. A. (1980): Induction of supernumerary tracheal buds and the stimulation of DNA synthesis in the embryonic chick lung and trachea by epidermal growth factor, J Embryol Exp Morphol, (vol. 60), pp.235-43. [307] Goldin, G. V.; Hindman, H. M. and Wessells, N. K. (1984): The role of cell proliferation and cellular shape change in branching morphogenesis of the embryonic mouse lung: analysis using aphidicolin and cytochalasins, J Exp Zool, (vol. 232), No. 2, pp.287-96. [308] Heine, U. I.; Munoz, E. F.; Flanders, K. C.; Roberts, A. B. and Sporn, M. B. (1990): Colocalization of TGF-beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis, Development, (vol. 109), No. 1, pp.29-36. [309] Pelton, R. W.; Saxena, B.; Jones, M.; Moses, H. L. and Gold, L. I. (1991): Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development, J Cell Biol, (vol. 115), No. 4, pp.1091-105. [310] Serra, R.; Pelton, R. W. and Moses, H. L. (1994): TGF beta 1 inhibits branching morphogenesis and N-myc expression in lung bud organ cultures, Development, (vol. 120), No. 8, pp.2153-61. [311] Serra, R. and Moses, H. L. (1995): pRb is necessary for inhibition of N-myc expression by TGF-beta 1 in embryonic lung organ cultures, Development, (vol. 121), No. 9, pp.3057-66. [312] Kokkinos, M. I.; Wafai, R.; Wong, M. K.; Newgreen, D. F.; Thompson, E. W. and Waltham, M. (2007): Vimentin and epithelial-mesenchymal transition in human breast cancer--observations in vitro and in vivo, Cells Tissues Organs, (vol. 185), No. 1-3, pp.191-203. [313] Bae, S. N.; Arand, G.; Azzam, H.; Pavasant, P.; Torri, J.; Frandsen, T. L. and Thompson, E. W. (1993): Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays, Breast Cancer Res Treat, (vol. 24), No. 3, pp.241-55. [314] Schwarz, J. K.; Bassing, C. H.; Kovesdi, I.; Datto, M. B.; Blazing, M.; George, S.; Wang, X. F. and Nevins, J. R. (1995): Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression, Proc Natl Acad Sci U S A, (vol. 92), No. 2, pp.483-7. [315] Petrocca, F.; Visone, R.; Onelli, M. R.; Shah, M. H.; Nicoloso, M. S.; de Martino, I.; Iliopoulos, D.; Pilozzi, E.; Liu, C. G.; Negrini, M.; Cavazzini, L.; Volinia, S.; Alder, H.; Ruco, L. P.; Baldassarre, G.; Croce, C. M. and Vecchione, A. (2008): E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer, Cancer Cell, (vol. 13), No. 3, pp.272-86. [316] Forrester, E.; Chytil, A.; Bierie, B.; Aakre, M.; Gorska, A. E.; Sharif-Afshar, A. R.; Muller, W. J. and Moses, H. L. (2005): Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis, Cancer Res, (vol. 65), No. 6, pp.2296-302. [317] Bierie, B.; Stover, D. G.; Abel, T. W.; Chytil, A.; Gorska, A. E.; Aakre, M.; Forrester, E.; Yang, L.; Wagner, K. U. and Moses, H. L. (2008): Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment, Cancer Res, (vol. 68), No. 6, pp.1809-19. [318] Yang, L.; Huang, J.; Ren, X.; Gorska, A. E.; Chytil, A.; Aakre, M.; Carbone, D. P.; Matrisian, L. M.; Richmond, A.; Lin, P. C. and Moses, H. L. (2008): Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis, Cancer Cell, (vol. 13), No. 1, pp.23-35. [319] Muller, H. and Helin, K. (2000): The E2F transcription factors: key regulators of cell proliferation, Biochim Biophys Acta, (vol. 1470), No. 1, pp.M1-12. [320] Tsushima, H.; Kawata, S.; Tamura, S.; Ito, N.; Shirai, Y.; Kiso, S.; Imai, Y.; Shimomukai, H.; Nomura, Y.; Matsuda, Y. and Matsuzawa, Y. (1996): High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression, Gastroenterology, (vol. 110), No. 2, pp.375-82. [321] De Wever, O. and Mareel, M. (2003): Role of tissue stroma in cancer cell invasion, J Pathol, (vol. 200), No. 4, pp.429-47. [322] Mollinari, C.; Kleman, J. P.; Saoudi, Y.; Jablonski, S. A.; Perard, J.; Yen, T. J. and Margolis, R. L. (2005): Ablation of PRC1 by small interfering RNA demonstrates that cytokinetic abscission requires a central spindle bundle in mammalian cells, whereas completion of furrowing does not, Mol Biol Cell, (vol. 16), No. 3, pp.1043-55. [323] Fabbro, M.; Zhou, B. B.; Takahashi, M.; Sarcevic, B.; Lal, P.; Graham, M. E.; Gabrielli, B. G.; Robinson, P. J.; Nigg, E. A.; Ono, Y. and Khanna, K. K. (2005): Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis, Dev Cell, (vol. 9), No. 4, pp.477-88. [324] Mollinari, C.; Kleman, J. P.; Jiang, W.; Schoehn, G.; Hunter, T. and Margolis, R. L. (2002): PRC1 is a microtubule binding and bundling protein essential to maintain the mitotic spindle midzone, J Cell Biol, (vol. 157), No. 7, pp.1175-86. [325] Martinez-Garay, I.; Rustom, A.; Gerdes, H. H. and Kutsche, K. (2006): The novel centrosomal associated protein CEP55 is present in the spindle midzone and the midbody, Genomics, (vol. 87), No. 2, pp.243-53. [326] Miki, T.; Smith, C. L.; Long, J. E.; Eva, A. and Fleming, T. P. (1993): Oncogene ect2 is related to regulators of small GTP-binding proteins, Nature, (vol. 362), No. 6419, pp.462-5. [327] Sano, M.; Genkai, N.; Yajima, N.; Tsuchiya, N.; Homma, J.; Tanaka, R.; Miki, T. and Yamanaka, R. (2006): Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients, Oncol Rep, (vol. 16), No. 5, pp.1093-8. [328] Shimo, A.; Nishidate, T.; Ohta, T.; Fukuda, M.; Nakamura, Y. and Katagiri, T. (2007): Elevated expression of protein regulator of cytokinesis 1, involved in the growth of breast cancer cells, Cancer Sci, (vol. 98), No. 2, pp.174-81. [329] Nishimura, Y. and Yonemura, S. (2006): Centralspindlin regulates ECT2 and RhoA accumulation at the equatorial cortex during cytokinesis, J Cell Sci, (vol. 119), No. Pt 1, pp.104-14. [330] Schmitz, A. A.; Govek, E. E.; Bottner, B. and Van Aelst, L. (2000): Rho GTPases: signaling, migration, and invasion, Exp Cell Res, (vol. 261), No. 1, pp.1-12. [331] Saito, S.; Liu, X. F.; Kamijo, K.; Raziuddin, R.; Tatsumoto, T.; Okamoto, I.; Chen, X.; Lee, C. C.; Lorenzi, M. V.; Ohara, N. and Miki, T. (2004): Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation, J Biol Chem, (vol. 279), No. 8, pp.7169-79. [332] Liu, X. F.; Ishida, H.; Raziuddin, R. and Miki, T. (2004): Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity, Mol Cell Biol, (vol. 24), No. 15, pp.6665-75. [333] Liu, X. F.; Ohno, S. and Miki, T. (2006): Nucleotide exchange factor ECT2 regulates epithelial cell polarity, Cell Signal, (vol. 18), No. 10, pp.1604-15. [334] Kawashima, T.; Bao, Y. C.; Nomura, Y.; Moon, Y.; Tonozuka, Y.; Minoshima, Y.; Hatori, T.; Tsuchiya, A.; Kiyono, M.; Nosaka, T.; Nakajima, H.; Williams, D. A. and Kitamura, T. (2006): Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors, J Cell Biol, (vol. 175), No. 6, pp.937-46. [335] Hayakawa, F. and Naoe, T. (2006): SFK-STAT pathway: an alternative and important way to malignancies, Ann N Y Acad Sci, (vol. 1086), pp.213-22. [336] Klampfer, L. (2008): The role of signal transducers and activators of transcription in colon cancer, Front Biosci, (vol. 13), pp.2888-99. [337] Howman, E. V.; Fowler, K. J.; Newson, A. J.; Redward, S.; MacDonald, A. C.; Kalitsis, P. and Choo, K. H. (2000): Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice, Proc Natl Acad Sci U S A, (vol. 97), No. 3, pp.1148-53. [338] Kalitsis, P.; Fowler, K. J.; Earle, E.; Griffiths, B.; Howman, E.; Newson, A. J. and Choo, K. H. (2003): Partially functional Cenpa-GFP fusion protein causes increased chromosome missegregation and apoptosis during mouse embryogenesis, Chromosome Res, (vol. 11), No. 4, pp.345-57. [339] Yang, Z. Y.; Guo, J.; Li, N.; Qian, M.; Wang, S. N. and Zhu, X. L. (2003): Mitosin/CENP-F is a conserved kinetochore protein subjected to cytoplasmic dynein-mediated poleward transport, Cell Res, (vol. 13), No. 4, pp.275-83. [340] Ausubel, F. M. (1987): Current protocols in molecular biology. [341] Sambrock, J., Fritsch, E. F., & Maniatis, T. (1989): Molecular Cloning: a laboratory manual.