Transformation by Polyomaviruses

Role of Tumor Suppressor Proteins
  • Daniel T. Simmons
Part of the Infectious Agents and Pathogenesis book series (IAPA)


Since its identification as a tumor virus, SV40 has been a favorite model for understanding the mechanism by which a DNA virus can control the state and growth properties of susceptible cells. From its humble beginnings, the polyomavirus tumor biology field has mushroomed into several new directions, most notably into tumor suppressors. These new branches are now buzzing with activity and touching or merging with other established disciplines including cell-cycle controls, oncogenes, and differentiation.


Tumor Suppressor Protein Simian Virus Polyoma Virus Retinoblastoma Gene Product Large Tumor Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brugge, J. S., and Butel, J. S., 1975, Role of simian virus 40 gene A function in maintenance of transformation, J. Virol. 15:619–635.PubMedGoogle Scholar
  2. 2.
    Kimura, G., and Itagaki, A., 1975, Initiation and maintenance of cell transformation by simian virus 40: A viral genetic property, Proc. Natl. Acad. Sci. USA 72:673–677.PubMedCrossRefGoogle Scholar
  3. 3.
    Martin, R. G., and Chou, J. Y, 1975, Simian virus 40 functions required for the establishment and maintenance of malignant transformation, J. Virol. 15:599–612.PubMedGoogle Scholar
  4. 4.
    Osborn, M., and Weber, K., 1975, Simian virus 40 gene A function and maintenance of transformation, J. Virol. 15:636–644.PubMedGoogle Scholar
  5. 5.
    Arthur, A. K., Höss, A., and Fanning, E., 1988, Expression of simian virus 40 T antigen if Escherichia coli: Localization of T-antigen origin DNA-binding domain to within 129 amino acids, J. Virol. 62:1999–2006.PubMedGoogle Scholar
  6. 6.
    Simmons, D. T., 1986, DNA-binding region of the simian virus 40 tumor antigen, J. Virol. 57:776–785.PubMedGoogle Scholar
  7. 7.
    Simmons, D. T., 1988, Geometry of the simian virus 40 large tumor antigen-DNA complex as probed by protease digestion, Proc. Natl. Acad. Sci. USA 85:2086–2090.PubMedCrossRefGoogle Scholar
  8. 8.
    Simmons, D. T., Loeber, G., and Tegtmeyer, P., 1990, Four major sequence elements of simian virus 40 large T antigen coordinate its specific and nonspecific DNA binding, J. Virol. 64:1973–1983.PubMedGoogle Scholar
  9. 9.
    Simmons, D. T., Wun-Kim, K., and Young, W., 1990, Identification of simian virus 40 T antigen residues important for specific and nonspecific binding to DNA and for helicase activity, J. Virol. 64:4858–4865.PubMedGoogle Scholar
  10. 10.
    Strauss, M., Argani, P., Mohr, I. J., and Gluzman, Y, 1987, Studies on the origin-specific DNA-binding domain of simian virus 40 large T antigen, J. Virol. 61:3326–3330.PubMedGoogle Scholar
  11. 11.
    Wun-Kim, K., and Simmons, D. T., 1990, Mapping of helicase and helicase substrate binding domains on simian virus 40 large T antigen, J. Virol. 64:2014–2020.PubMedGoogle Scholar
  12. 12.
    Bradley, M. K., Smith, T. F., Lathrop, R. H., Livingston, D. M., and Webster, T. A., 1987, Consensus topography in the ATP binding site of the simian virus 40 and polyomavirus large tumor antigens, Proc. Natl. Acad. Sci. USA 84:4026–4030.PubMedCrossRefGoogle Scholar
  13. 13.
    Bradley, M. K., 1990, Activation of ATPase activity of simian virus 40 large T antigen by the covalent affinity analog of ATP, fluorosulfonylbenzoyl 5′-adenosine, J. Virol. 64:4939–4947.PubMedGoogle Scholar
  14. 14.
    Brady, J. N., Bolen, J. B., Radonovich, M., Salzman, N., and Khoury, G., 1984, Stimulation of simian virus 40 late gene expression by simian virus 40 tumor antigen, Proc. Natl. Acad. Sci. USA 81:2040–2044.PubMedCrossRefGoogle Scholar
  15. 15.
    Keller, J. M., and Alwine, J. C., 1984, Activation of the SV40 late promoter: Direct effects of T antigen in the absence of viral DNA replication, Cell 36:381–389.PubMedCrossRefGoogle Scholar
  16. 16.
    Alwine, J. C., 1985, Transient gene expression control: Effects of transfected DNA stability and irans-activation by viral early proteins, Mol. Cell. Biol. 5:1034–1042.PubMedGoogle Scholar
  17. 17.
    Schutzbank, T., Robinson, R., Oren, M., and Levine, A. J., 1982, SV40 large tumor antigen can regulate some cellular transcripts in a positive fashion, Cell 30:481–490.PubMedCrossRefGoogle Scholar
  18. 18.
    Scott, M. R. D., Westphal, K.-H., and Rigby, P. W. J., 1983, Activation of mouse genes in transformed cells, Cell 34:557–567.PubMedCrossRefGoogle Scholar
  19. 19.
    Segawa, K., and Yamaguchi, N., 1987, Induction of c-Ha-ras transcription in rat cell by simian large T antigen, Mol. Cell. Biol. 7:556–559.PubMedGoogle Scholar
  20. 20.
    Hiscott, J., Wong, A., Alper, D., and Xanthoudakis, S., 1988, Trans activation of type I interferon promoters by simian virus 40 T antigen, Mol. Cell. Biol. 8:3397–3405.PubMedGoogle Scholar
  21. 21.
    Srinivasan, A., Peden, K. W. C., and Pipas, J. M, 1989, The large tumor antigen of simian virus 40 encodes at least two distinct transforming functions, J. Virol. 63:5459–5463.PubMedGoogle Scholar
  22. 22.
    Scheidtmann, K. H., Echle, B., and Walter, G., 1982, Simian virus 40 large T antigen is phosphorylated at multiple sites clustered in two separate regions, J. Virol. 44:116–133.PubMedGoogle Scholar
  23. 23.
    Scheidtmann, K.-H., 1986, Phosphorylation of simian virus 40 large T antigen: Cytoplasmic and nuclear phosphorylation sites differ in their metabolic stability, Virology 150:85–95.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen, Y.-R., Lees-Miller, S. P., Tegtmeyer, P., and Anderson, C. W., 1991, The human DNA-activated protein kinase phosphorylates simian virus 40 T antigen at amino-and carboxy-terminal sites, J. Virol. 65:5131–5140.PubMedGoogle Scholar
  25. 25.
    Simmons, D. T., Chou, W., and Rodgers, K., 1986, Phosphorylation downregulates the DNA-binding activity of simian virus 40 T antigen, J. Virol. 60:888–894.PubMedGoogle Scholar
  26. 26.
    Grasser, E A., Mann, K., and Walter, G., 1987, Removal of serine phosphates from simian virus 40 large T antigen increases its ability to stimulate DNA replication in vitro but has no effect on ATPase and DNA binding, J. Virol. 61:3373–3380.PubMedGoogle Scholar
  27. 27.
    Mohr, I. J., Stillman, B., and Gluzman, Y, 1987, Regulation of SV40 DNA replication of phosphorylation of T antigen, EMBO J. 6:153–160.PubMedGoogle Scholar
  28. 28.
    Schneider, J., and Fanning, E., 1988, Mutations in the phosphorylation sites of simian virus 40 (SV40) T antigen alter its origin DNA-binding specificity for sites I or II and affect SV40 DNA replication activity, J. Virol. 62:1598–1605.PubMedGoogle Scholar
  29. 29.
    Moarefi, I. F., Small, D., Gilbert, I., Hopfner, M., Randall, S. K., Schneider, C., Russo, A. A. R., Ramsperger, U., Arthur, A., Stahl, H., Kelly, T. J., and Fanning, E., 1993, Mutation of the cyclin-dependent kinase phosphorylation site in simian virus 40 (SV40) large T antigen specifically blocks SV40 origin DNA unwinding, J. Virol. 67:4992–5002.PubMedGoogle Scholar
  30. 30.
    McVey, D., Ray, S., Gluzman, Y., Berger, L., Wildeman, A. G., Marshak, D. R., and Tegtmeyer, P., 1993, cdc2 phosphorylation of threonine 124 activates the origin-unwinding functions of simian virus 40 T antigen, J. Virol. 67:5206–5215.PubMedGoogle Scholar
  31. 31.
    McVey, D., Brizuela, L., Mohr, I., Marshak, D. R., Gluzman, Y., and Beach, D., 1989, Phosphorylation of large tumour antigen by cdc2 stimulates SV40 DNA replication, Nature 341:503–507.PubMedCrossRefGoogle Scholar
  32. 32.
    Prives, C., 1990, The replication functions of SV40 T antigen are regulated by phosphorylation, Cell 61:735–738.PubMedCrossRefGoogle Scholar
  33. 33.
    Fanning, E., and Knippers, R., 1992, Structure and function of simian virus 40 large tumor antigen, Annu. Rev. Biochem. 61:55–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Yaciuk, P., Carter, M. C., Pipas, J. M., and Moran, E., 1991, Simian virus 40 large-T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products, Mol. Cell. Biol. 11:2116–2124.PubMedGoogle Scholar
  35. 35.
    Schmieg, F. I., and Simmons, D. T., 1988, Characterization of the in vitro interaction between SV40 T antigen and p53: Mapping the p53 binding site, Virology 164:132–140.PubMedCrossRefGoogle Scholar
  36. 36.
    Mole, S. E., Gannon J. V., Ford, M. J., and Lane, D. P., 1987, Structure and function of large T antigen, Phil. Trans. R. Soc. Lond. [B] 317:455–469.CrossRefGoogle Scholar
  37. 37.
    Manfredi, J. J., and Prives, C., 1990, Binding of p53 and p105-Rb is not sufficient for oncogenic transformation by a hybrid polyomavirus-simian virus 40 large T antigen, J. Virol. 64:5250–5259.PubMedGoogle Scholar
  38. 38.
    Kierstead, T. D., and Tevethia, M. J., 1993, Association of p53 binding and immortalization of primary C57BL/6 mouse embryo fibroblasts by using simian virus 40 T-antigen mutants bearing internal overlapping deletion mutations, J. Virol. 67:1817–1929.PubMedGoogle Scholar
  39. 39.
    DeCaprio, J. A., Ludlow, J. W., Lynch, D., Furukawa, Y., Griffin, J., Piwnica-Worms, H., Huang, C.-M., and Livingston, D. M., 1989, The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element, Cell 58:1085–1095.PubMedCrossRefGoogle Scholar
  40. 40.
    Montano, X., Millikan, R., Milhaven, J. M., Newsome, D. A., Ludlow, J. W., Arthur, A. K., Fanning, E., Bikel, I., and Livingston, D. M., 1990, Simian virus 40 small tumor antigen and an amino-terminal domain of large tumor antigen share a common transforming function, Proc. Natl Acad. Sci. USA 87:7448–7452.PubMedCrossRefGoogle Scholar
  41. 41.
    Harlow, E., Whyte, P., Franza, B. R. J., and Schley, C., 1986, Association of adenovirus early region LA with cellular polypeptides, Mol Cell. Biol 6:1579–1589.PubMedGoogle Scholar
  42. 42.
    Whyte, P., Buchkovick, 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 Ela proteins bind to the retinoblastoma gene product, Nature 334:124–129.PubMedCrossRefGoogle Scholar
  43. 43.
    DeCaprio, J. A., Ludlow, J. W., Figge, J., Shew, J.-Y., Huang, C.-M., Lee, W.-H., Marsilio, E., Paucha, E., and Livingston, D. M., 1988, SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene, Cell 54:275–283.PubMedCrossRefGoogle Scholar
  44. 44.
    Dyson, N., Buchkovich, K., Whyte, P., and Harlow, E., 1989, The cellular 107 kD protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus, Cell 58:249–255.PubMedCrossRefGoogle Scholar
  45. 45.
    Kalderon, D., and Smith, A. E., 1984, In vitro mutagenesis of a putative DNA binding domain of SV40 large-T, Virology 139:109–137.PubMedCrossRefGoogle Scholar
  46. 46.
    Ewen, M. E., Ludlow, J. W., Marsilio, E., DeCaprio, J. A., Millikan, R. C., Cheng, S. H., Paucha, E., and Livingston, D. M., 1989, An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both pllORb and a second cellular protein, pl20, Cell 58:257–267.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen, S., and Paucha, E., 1990, Identification of a region of simian virus 40 large T antigen required for cell transformation, J. Virol 64:3350–3357.PubMedGoogle Scholar
  48. 48.
    Riley, D. J., Lee, E. Y.-H. P., and Lee, W.-H., 1994, The retinoblastoma protein: More than a tumor suppressor, Annu. Rev. Cell. Biol 10:1–29.PubMedCrossRefGoogle Scholar
  49. 49.
    Buchkovich, K., Duffy, L. A., and Harlow, E., 1989, The retinoblastoma protein is phosphory-lated during specific phases of the cell cycle, Cell 58:1097–1105.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen, P. L., Scully, P., Shew, J.-Y., Wang, J. Y. J., and Lee, W.-H., 1989, Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation, Cell 58:1193–1198.PubMedCrossRefGoogle Scholar
  51. 51.
    DeCaprio, J. A., Furukawa, Y., Ajchenbaum, F., Griffin, J. D., and Livingston, D. M., 1992, The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression, Proc. Natl Acad. Sci. USA 89:1795–1798.PubMedCrossRefGoogle Scholar
  52. 52.
    Furukawa, Y., DeCaprio, J. A., Freedman, A., Kanakura, Y., Nakamura, M., Ernst, T. J., Livingston, D. M., and Griffin, J. D., 1990, Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and non-cycling human hematopoietic cells, Proc. Natl Acad. Sci. USA 87:2770–2774.PubMedCrossRefGoogle Scholar
  53. 53.
    Lee, W.-H., Hollingworth, R. E. J., Qian, Y-W., Chen, P.-L., Hong, F., and Lee, E. Y.-H. P., 1991, Rb protein as a cellular “corral” for growth promoting proteins, Cold Spring Harbor Symp. Quant. Biol. 56:211–217.PubMedCrossRefGoogle Scholar
  54. 54.
    Lees, J. A., Buchkovich, K.J., Marshak, D. R., Anderson, C. W., and Harlow, E., 1991, The retinoblastoma protein is phosphorylated on multiple sites by human cdc2, EMBOJ. 10:4279–4290.Google Scholar
  55. 55.
    Lin, B. T.-Y., Gruenwald, S., Morla, A. O., Lee, W.-H., and Wang J. Y J., 1991, Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase, EMBO J. 10:857–864.PubMedGoogle Scholar
  56. 56.
    Ludlow, J. W., Shen, J., Pipas, J. M., Livingston, D. M., and DeCaprio, J. A., 1990, The retinoblastoma susceptibility gene product undergoes cell-cycle-dependent dephosphorylation and binding to and release from SV40 large T antigen, Cell 60:387–396.PubMedCrossRefGoogle Scholar
  57. 57.
    Chellappan, S., Kraus, V. B., Kroger, B., Munger, K., Phelps, W. C., Nevins, J. R., and Howley, P. M., 1992, Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product, Proc. Natl. Acad. Sci. USA 89:4549–4553.PubMedCrossRefGoogle Scholar
  58. 58.
    Durfee, T., Becherer, K., Chen, P.-L., Yeh, S.-H., and Yang, Y, 1993, The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit, Genes Dev. 7:555–569.PubMedCrossRefGoogle Scholar
  59. 59.
    Alberts, A. S., Thorburn, A. M., Shenolikar, S., Mumby, M. C., and Framisco, J. R., 1993, Regulation of cell cycle progression and nuclear affinity of the retinoblastoma protein by protein phosphatases, Proc. Natl. Acad. Sci. USA 90:388–392.PubMedCrossRefGoogle Scholar
  60. 60.
    Ludlow, Y W., Glendening, C. L., Livingston, D. M., and DeCaprio, J. A., 1993, Specific enzymatic dephosphorylation of the retinoblastoma protein, Mol. Cell. Biol. 13:367–372.PubMedGoogle Scholar
  61. 61.
    Ludlow, J. W., DeCaprio, J. A., Huang, C.-M., Lee, W.-H., Paucha, E., and Livingston, D. M., 1989, SV40 large T-antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family, Cell 56:57–65.PubMedCrossRefGoogle Scholar
  62. 62.
    Goodrich, D. W., Wang, N. P., Qian, Y.-W., Lee, E. Y-H. P., and Lee, W.-H., 1991, The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle, Cell 67:293–302.PubMedCrossRefGoogle Scholar
  63. 63.
    Nevins, J. R., 1992, A link between the Rb tumor suppressor protein and viral oncoproteins, Science 258:424–429.PubMedCrossRefGoogle Scholar
  64. 64.
    Rustgi, A. K., Dyson, N., and Bernards, R., 1991, Amino-terminaldomains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product, Nature 352:541–544.PubMedCrossRefGoogle Scholar
  65. 65.
    Dou, Q.-P., Markell, P. J., and Pardee, A. B., 1992, Thymidine kinase transcription is regulated at the G1/S phase by a complex that contains retinoblastoma-like protein and a cdc2 kinase, Proc. Natl. Acad. Sci. USA 89:3256–3260.PubMedCrossRefGoogle Scholar
  66. 66.
    Pearson, A. B., Nasheuer, H.-P., and Wang, T. S.-E, 1991, Human DNA polymerase a gene: Sequences controlling expression in cycling and serum-stimulated cells. Mol. Cell. Biol. 11:2081–2095.PubMedGoogle Scholar
  67. 67.
    Dyson, N., Howley, P. M., Munger, K., and Harlow, E., 1989, The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product, Science 243:934–936.PubMedCrossRefGoogle Scholar
  68. 68.
    Mueller, H., Lukas, J., Schneider, A., Warthoe, P., Bartek, J., Eilers, M., and Strauss, M., 1994, Cyclin D1 expression is regulated by the retinoblastoma protein, Proc. Natl. Acad. Sci. USA 91:2945–2949.CrossRefGoogle Scholar
  69. 69.
    Lukas, J., Muller, H., Bartkova, J., Spitkovsky, D., Kjerulff, A. A., Jansen-Durr, P., Strauss, M., and Bartek, J., 1994, DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell’s requirement for cyclin Dl function in G1, J. Cell Biol. 125:625–638.PubMedCrossRefGoogle Scholar
  70. 70.
    Bartkova, J., Lukas, J., Müller, H., Lutzhoft, D., Strauss, M., and Bartek, J., 1994, Cyclin Dl protein expression and function in human breast cancer, Int. J. Cancer 57:353–361.PubMedCrossRefGoogle Scholar
  71. 71.
    Mancini, M., Shan, B., Nickerson, J., Penman, S., and Lee, W.-H., 1994, The retinoblastoma gene product is a cell-cycle dependent, nuclear-matrix associated protein, Proc. Natl. Acad. Sci. USA 91:418–422.PubMedCrossRefGoogle Scholar
  72. 72.
    Ewen, M. E., Xing, Y G., Lawrence, J. B., and Livingston, D. M., 1991, Molecular cloning, chromosomal mapping, and expression of the cDNA for pl07, a retinoblastoma gene product-related protein, Cell 66:1155–1164.PubMedCrossRefGoogle Scholar
  73. 73.
    Hannon, G.J., Demetrick, D., and Beach, D., 1993, Isolation of the Rb-related pl30 through its interaction with CDK2 and cyclins, Genes Dev. 7:2378–2391.PubMedCrossRefGoogle Scholar
  74. 74.
    Mayol, X., Grana, X., Baldi, A. M. S., Hu, Q., and Giordano, A., 1993, Cloning of a new member of the retinoblastoma gene family (pRB2) which binds to the E1A transforming domain, Oncogene 8:2561–2566.PubMedGoogle Scholar
  75. 75.
    Ewen, M. E., Faha, B., Harlow, E., and Livingston, D. M., 1992, Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins. Science 255:85–87.PubMedCrossRefGoogle Scholar
  76. 76.
    Linzer, D. I. H., Maltzman, W., 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 17:43–52.PubMedCrossRefGoogle Scholar
  77. 77.
    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. 31:463–471.PubMedGoogle Scholar
  78. 78.
    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. 31:472–483.PubMedGoogle Scholar
  79. 79.
    Lane, D. P., and Crawford, L. V., 1979, T-antigen is bound to a host protein in SV40 transformed cells, Nature 278:261–263.PubMedCrossRefGoogle Scholar
  80. 80.
    Deppert, W., and Steinmayer, T., 1989, Metabolic stabilization of p53 in SV40-transformed cells correlates with expression of the transformed phenotype but is independent from complex formation with SV40 large T antigen, Curr. Top. Microbiol. Immunol. 144:77–84.PubMedCrossRefGoogle Scholar
  81. 81.
    Tiemann, F., and Deppert, W., 1994, Stabilization of the tumor suppressor p53 during cellular transformation by simian virus 40: Influence of viral and cellular factors and biological consequences, J. Virol. 68:2869–2878.PubMedGoogle Scholar
  82. 82.
    Lin, J.-Y., and Simmons, D. T., 1991, The ability of large T antigen to complex with p53 is necessary for the increased life span and partial transformation of human cells by simian virus 40, J. Virol. 65:6447–6453.PubMedGoogle Scholar
  83. 83.
    Zhu, J., Abate, M., Rice, P. W., and Cole, C. N., 1991, The ability of simian virus 40 large T antigen to immortalize primary mouse embryo fibroblasts cosegregates with its ability to bind to p53, J. Virol. 65:6872–6880.PubMedGoogle Scholar
  84. 84.
    Tiemann, F., and Deppert, W., 1994, Immortalization of BALB/c mouse embryo fibroblasts alters SV40 large T-antigen interactions with the tumor suppressor p53 and results in a reduced SV40 transformation-efficiency, Oncogene 9:1907–1915.PubMedGoogle Scholar
  85. 85.
    Finlay, C. A., Hinds, W., and Levine, A. J., 1989, The p53 protooncogene can act as a suppressor of transformation, Cell 57:1083–1093.PubMedCrossRefGoogle Scholar
  86. 86.
    Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O., and Oren, M., 1989, Wild-type p53 can inhibit oncogene-mediated focus formation, Proc. Natl. Acad. Sci. USA 86:8763–8767.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen, P.-L., Chen, Y., Bookstein, R., and Lee, W.-H., 1990, Genetic mechanisms of tumor suppression by the human p53 gene, Science 250:1576–1580.PubMedCrossRefGoogle Scholar
  88. 88.
    Diller, L., Kassel, J., Nelson, C. E., Gryka, M. A., Litwak, G., Gebhardt, M., Bressac, B., Ozturk, M., Baker, S. J., and Vogelstein, B., 1990, p53 functions as a cell cycle control protein in osteosarcomas, Mol. Cell. Biol. 10:5772–5781.PubMedGoogle Scholar
  89. 89.
    Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. V., and Vogelstein, B., 1990, Suppression of human colorectal carcinoma cell growth by wild-type p53, Science 249:912–915.PubMedCrossRefGoogle Scholar
  90. 90.
    Johnson, P., Gray, D., Mowat, M., and Benchimol, S., 1991, Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells, Mol. Cell. Biol. 11:1–11.PubMedGoogle Scholar
  91. 91.
    Yonish-Rouach, E., Resnitzky, D., Lotem, J., Sachs, L., Kimchi, A., and Oren, M., 1991, Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6, Nature 352:345–347.PubMedCrossRefGoogle Scholar
  92. 92.
    Fukasawa, K., Sakoulas, G., Pollack, R. E., and Chen, S., 1991, Excess wild-type p53 blocks initiation and maintenance of simian virus 40 transformation, Mol Cell. Biol. 11:3472–3483.PubMedGoogle Scholar
  93. 93.
    Finlay, C. A., 1993, The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth, Mol. Cell. Biol. 13:301–306.PubMedGoogle Scholar
  94. 94.
    Mercer, W. E., Shields, M. T., Lin, D., Appella, E., and Ullrich, S. J., 1991, Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen expression, Proc. Natl. Acad. Sci. USA 88:1958–1962.PubMedCrossRefGoogle Scholar
  95. 95.
    Michalovitz, D., Halevy, O., and Oren, M., 1990, Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53, Cell 52:671–680.CrossRefGoogle Scholar
  96. 96.
    Martinez, J., Georgoff, I., Martinez, J., and Levine, A. J., 1991, Cellular localization and cell cycle regulation by a temperature sensitive p53 protein, Genes Dev. 5:151–159.PubMedCrossRefGoogle Scholar
  97. 97.
    Ginsberg, D., Michalovitz, D. M., Ginsberg, D., and Oren, M., 1991, Induction of growth arrest by a temperature-sensitive p53 mutant is correlated with increased nuclear localization and decreased stability of the protein, Mol Cell. Biol. 11:582–585.PubMedGoogle Scholar
  98. 98.
    Harvey, D., and Levine, A. J., 1991, p53 alteration is a common event in the spontaneous immortalization of primary BALB/C murine embryo fibroblasts, Genes Dev. 5:2375–2385.PubMedCrossRefGoogle Scholar
  99. 99.
    Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W., 1991, Participation of p53 protein in the cellular response to DNA damage, Cancer Res. 51:6304–6311.PubMedGoogle Scholar
  100. 100.
    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. USA 89:7491–7495.PubMedCrossRefGoogle Scholar
  101. 101.
    Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F. Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., and Fornace, A. J., Jr., 1992, A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia, Cell 71:587–597.PubMedCrossRefGoogle Scholar
  102. 102.
    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 356:215–221.PubMedCrossRefGoogle Scholar
  103. 103.
    Levine, A. J., 1993, The tumor suppressor genes, Annu. Rev. Biochem. 62:623–651.PubMedCrossRefGoogle Scholar
  104. 104.
    Moll, U. M., Riou, G., and Levine, A. J., 1992, Two distinct mechanisms alter p53 in breast cancer: Mutation and nuclear exclusion, Proc. Natl. Acad. Sci. USA 89:7262–7266.PubMedCrossRefGoogle Scholar
  105. 105.
    Momand, J., Zambetti, G., Olson, D. C., George, D., and Levine, A. J., 1992, The mdm2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transacti-vation, Cell 69:1237–1245.PubMedCrossRefGoogle Scholar
  106. 106.
    Werness, B. A., Levine, A. J., and Howley, P. M., 1990, Association of human papillomavirus types 16 and 18 E6 proteins with p53, Science 248:76–79.PubMedCrossRefGoogle Scholar
  107. 107.
    Weintraub, H., Hauschka, S., and Tapscott, S. J., 1991, The MCK enhancer contains a p53 responsive element, Proc. Natl. Acad. Sci. USA 88:4570–4571.PubMedCrossRefGoogle Scholar
  108. 108.
    Farmer, G., Bargonetti, J., Zhu, H., Friedman, P., Prywes, R., and Prives, C., 1992, Wild-type p53 activates transcription in vitro, Nature 358:83–86.PubMedCrossRefGoogle Scholar
  109. 109.
    El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W., and Vogelstein, B., 1992, Human genomic DNA sequences define a consensus binding site for p53, Nature Genet. 1:44–49.CrossRefGoogle Scholar
  110. 110.
    Fields, S., and Jang, S. K., 1990, Presence of a potent transcription activating sequence in the p53 protein, Science 249:1046–1049.PubMedCrossRefGoogle Scholar
  111. 111.
    Raycroft, L., Wu, H., and Lozano, G., 1990, Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene, Science 249:1049–1051.PubMedCrossRefGoogle Scholar
  112. 112.
    Thut, C. J., Chen, J.-L., Klemm, R., and Tjian, R., 1995, p53 transcriptional activation mediated by coactivators TAF 40 and TAF 60, Science 267:100–104.PubMedCrossRefGoogle Scholar
  113. 113.
    Cho, Y., Gorina, S. Jeffrey, P. D., and Pavletich, N. P., 1994, Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations, Science 265:346–355.PubMedCrossRefGoogle Scholar
  114. 114.
    Barak, Y., Juven, T., Haffner, R., and Oren, M., 1993, mdm2 expression is induced by wild-type p53 activity, EMBOJ. 12:461–468.Google Scholar
  115. 115.
    Wu, X., Bayle, H., Olson, D., and Levine, A.J., 1993, The p53-mdm-2 autoregulatory feedback loops, Genes Dev. 7:1126–1132.PubMedCrossRefGoogle Scholar
  116. 116.
    Chen, C.-Y., Oliner, J. D., Zhan, Q., Fornace, A. J., Vogelstein, B., and Kastan, M. B., 1994, Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway, Proc. Natl. Acad. Sci. USA 91:2684–2688.PubMedCrossRefGoogle Scholar
  117. 117.
    Perry, M. E., Piette, J., Zawadzki, J. A., Harvey, D., and Levine, A.J., 1993, The mdm-2 gene is induced in response to UV light in a p53-dependent manner, Proc. Natl Acad. Sci. USA 90:11623–11627.PubMedCrossRefGoogle Scholar
  118. 118.
    Marston, N. J., Crook, T., and Vousden, K. H., 1994, Interaction of p53 with MDM2 is independent of E6 and does not mediate wild type transformation suppressor function, Oncogene 9:2707–2716.PubMedGoogle Scholar
  119. 119.
    El-Deiry, W. S., Tokino, T., Velculescu, V E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, E., Kinzler, K. W., and Vogelstein, B., 1993, WAF1, a potential mediator of p53 tumor suppression, Cell 75:817–825.PubMedCrossRefGoogle Scholar
  120. 120.
    Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K., and Elledge, S. J., 1993, The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases, Cell 75:805–816.PubMedCrossRefGoogle Scholar
  121. 121.
    Xiong, Y., Hannon, G. J., Zhang, H., Casso, D., Kobayashi, R., and Beach, D., 1993, p21 is a universal inhibitor of cyclin kinases, Nature 366:701–704.PubMedCrossRefGoogle Scholar
  122. 122.
    Norbury, C., and Nurse, P., 1992, Animal cell cycles and their control, Annu. Rev. Biochem. 61:441–470.PubMedCrossRefGoogle Scholar
  123. 123.
    Waga, S., Hannon, G. J., Beach, D., and Stillman, B., 1994, The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA, Nature 369:574–578.PubMedCrossRefGoogle Scholar
  124. 124.
    Dutta, A., Ruppert, J. M., Aster, J. C., and Winchester, E., 1993, Inhibition of DNA replication factor RPA by p53, Nature 365:79–82.PubMedCrossRefGoogle Scholar
  125. 125.
    Zhigang, H., Brinton, B. T., Greenblatt, J., Hassell, J. A., and Ingles, C.J., 1993, The transactiva-tor proteins VP16 and GAL4 bind replication factor A, Cell 73:1223–1232.CrossRefGoogle Scholar
  126. 126.
    Rong, L., and Botchan, M. R., 1993, The acidic transcriptional activation domains of VP16 and p53 bind the cellular replication protein A and stimulate in vitro BPV-1 DNA replication, Cell 73:1207–1221.CrossRefGoogle Scholar
  127. 127.
    Crook, T., Marston, N.J., Sara, E. A., and Vousden, K. H., 1994, Transcriptional activation by p53 correlates with suppression of growth but not transformation, Cell 79:817–827.PubMedCrossRefGoogle Scholar
  128. 128.
    Smith, M. L., Chen, I.-T., Zhan, Q., Bae, I., Chen, C.-Y., Gilmer, T. M., Kastan, M. B., O’Connor, P. M., and Fornace, A. J. J., 1994, Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen, Science 266:1376–1380.PubMedCrossRefGoogle Scholar
  129. 129.
    Zambetti, G. P., and Levine, A. J., 1993, A comparison of the biological activities of wild-type and mutant p53, FASEBJ. 7:855–865.Google Scholar
  130. 130.
    Debbas, M., and White, E., 1993, Wild-type p53 mediates apoptosis by E1A which is inhibited by E1B, Genes Dev. 7:546–554.PubMedCrossRefGoogle Scholar
  131. 131.
    Chiou, S.-K., Tseng, C.-C., Rao, L., and White, E., 1994, Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells, J. Virol. 68:6553–6566.PubMedGoogle Scholar
  132. 132.
    Lowe, S. W., Jacks, T., Housman, D. E., and Ruley, H. E., 1994, Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells, Proc. Natl. Acad. Sci. USA 91:2026–2030.PubMedCrossRefGoogle Scholar
  133. 133.
    Lowe, S. W., Ruley, H. E., Jacks, T., and Housman, D. E., 1993, p53-dependent apoptosis modulates the cytoxicity of anticancer agents, Cell 74:957–967.PubMedCrossRefGoogle Scholar
  134. 134.
    Lowe, S. W., Bodis, S., McClatchey, A., Remington, L., Ruley, H. E., Fisher, D. E., Housman, D. E., and Jacks, T., 1994, p53 status and the efficacy of cancer therapy in vivo, Science 266:807–810.PubMedCrossRefGoogle Scholar
  135. 135.
    Bargonetti, J., Reynisdottir, I., Friedman, P. N., and Prives, C., 1992, Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53, Genes Dev. 6:1886–1898.PubMedCrossRefGoogle Scholar
  136. 136.
    Mietz, J. A., Unger, T., Huibregtse, J. M., and Howley, P. M., 1992, The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein, EMBOJ. 11:5013–5020.Google Scholar
  137. 137.
    Jiang, D., Srinivasan, A., Lozano, G., and Robbins, P. D., 1993, SV40 T antigen abrogates p53-mediated transcriptional activity, Oncogene 8:2805–2812.PubMedGoogle Scholar
  138. 138.
    Michalovitz, D. M., Yehiely, F., Gottlieb, E., and Oren, M., 1991, Simian virus 40 can overcome the antiproliferative effect of wild-type p5B in the absence of stable large T antigen-p53 binding, J. Virol. 65:4160–4168.Google Scholar
  139. 139.
    McCarthy, S. A., Symonds, H. S., and Van-Dyke, T., 1994, Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53, Proc. Natl. Acad. Sci. USA 91:3979–3983.PubMedCrossRefGoogle Scholar
  140. 140.
    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. 63:739–746.PubMedGoogle Scholar
  141. 141.
    Milner, J., and Medcalf, E. A., 1991, Cotranslation of activated mutant p53 with wild-type drives the wild-type p53 protein into the mutant conformation, Cell 65:765–774.PubMedCrossRefGoogle Scholar
  142. 142.
    Milner, J., Medcalf, E. A., and Cook, A. C., 1991, Tumor suppressor p53: Analysis of wild-type and mutant p53 complexes, Mol. Cell. Biol. 11:12–19.PubMedGoogle Scholar
  143. 143.
    Dittmer, D., Pati, S., Zambetti, G., Ghu, S., Teresky, A. K., Moore, M., Finlay, C., and Levine, A. J., 1993, p53 gain of function mutations, Nature Genet. 4:42–45.PubMedCrossRefGoogle Scholar
  144. 144.
    Friedman, P. N., Kern, S. E., Vogelstein, B., and Prives, C., 1990, Wild-type, but not mutant, human p53 proteins inhibit the replication activities of simian virus 40 large tumor antigen, Proc. Natl Acad. Sci. USA 87:9275–9279.PubMedCrossRefGoogle Scholar
  145. 145.
    Kienzle, H., Baack, M., and Knippers, R., 1989, Effects of the cellular p53 protein on simian-virus-40-T-antigen-catalyzed DNA unwinding in vitro, Eur. J. Biochem. 184:181–186.PubMedCrossRefGoogle Scholar
  146. 146.
    Wang, E. H., Friedman, P. N., and Prives, C., 1989, The murine p53 protein blocks replication of SV40 DNA in vitro by inhibiting the initiation functions of SV40 large T antigen, Cell 57:379–392.PubMedCrossRefGoogle Scholar
  147. 147.
    Amin, A. A., Murakami, Y., and Hurwitz, J., 1994, Initiation of DNA replication by simian virus 40 T antigen is inhibited by the pl07 protein, J. Biol. Chem. 269:7735–7743.PubMedGoogle Scholar
  148. 148.
    Barbeau, D., Marcellus, R. C., Bacchetti, S., Bayley, S. T., and Branton, P. E., 1992, Quantitative analysis of regions of adenovirus E1A products involved in interactions with cellular proteins, Biochem. Cell Biol. 70:1123–1124.PubMedCrossRefGoogle Scholar
  149. 149.
    Wang, H. G., Rikitake, Y., Carter, M. C., Yaciuk, P., Abraham, S. E., Zerler, B., and Moran, E., 1993, Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth, J. Virol. 67:476–488.PubMedGoogle Scholar
  150. 150.
    Eckner, R., Ewen, M. E., Newsome, D., Gedes, M., DeCaprio, J. A., Lawrence, J. B., and Livingston, D. M., 1994, Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor, Genes Dev. 8:869–884.PubMedCrossRefGoogle Scholar
  151. 151.
    Caruso, M., Martelli, F., Giordano, A., and Felsani, A., 1993, Regulation of MyoD gene transcription and protein function by the transforming domains of the adenovirus E1A oncoprotein, Oncogene 8:267–278.PubMedGoogle Scholar
  152. 152.
    Zhu, J., Rice, P. W., Gorsch, L., Abate, M., and Cole, C. N., 1992, Transformation of a continuous rat embryo fibroblast cell line requires three separate domains of simian virus 40 large T antigen, J. Virol. 66:2780–2791.PubMedGoogle Scholar
  153. 153.
    Quartin, R. S., Cole, C. N., Pipas, J. M., and Levine, A. J., 1994, The amino-terminal functions of the simian virus 40 large T antigen are required to overcome wild-type p53-mediated growth arrest of cells, J. Virol. 68:1334–1341.PubMedGoogle Scholar
  154. 154.
    Cavender, J. E., Conn, A., Epier, M., Lacko, H., and Tevethia, M. J., 1995, Simian virus 40 large T antigen contains two independent activities that cooperate with a ras oncogene to transform rat embryo fibroblasts, J. Virol. 69:923–934.PubMedGoogle Scholar
  155. 155.
    Dickmanns, A., Zietvogel, A., Simmersbach, E., Weber, R., Arthur, A. K., Dehde, S., Wildeman, A. G., and Fanning, E., 1994, The kinetics of simian virus 40-induced progression of quiescent cells into S phase depend on four independent functions of large T antigen, J. Virol. 68:5496–5508.PubMedGoogle Scholar
  156. 156.
    Sompayrac, L., and Danna, K.J., 1988, A new SV40 mutant that encodes a small fragment of T antigen transforms established rat and mouse cells, Virology 163:391–396.PubMedCrossRefGoogle Scholar
  157. 157.
    Sompayrac, L., and Danna, K.J., 1991, The amino-terminal 147 amino acids of SV40 large T antigen transform secondary rat embryo fibroblasts, Virology 181:412–415.PubMedCrossRefGoogle Scholar
  158. 158.
    Asselin, C., and Bastin, M., 1985, Sequences from polyomavirus and simian virus 40 large T genes capable of immortalizing primary rat embryo fibroblasts, J. Virol. 56:958–968.PubMedGoogle Scholar
  159. 159.
    Thompson, D. L., Kalderon, D., Smith, A. E., and Tevethia, M. J., 1990, Dissociation of Rbbinding and anchorage-independent growth from immortalization and tumorigenicity using SV40 mutants producing N-terminally truncated large T antigens, Virology 178:15–34.PubMedCrossRefGoogle Scholar
  160. 160.
    Dornreiter, I., Hoss, A., Arthur, A. K., and Fanning, E., 1990, SV40 T antigen binds directly to the catalytic subunit of DNA polymerase a, EMBO J. 9:3329–3336.PubMedGoogle Scholar
  161. 161.
    Dornreiter, I., Erdile, L. F., Gilbert, I. U., von Winkler, D., Kelly, T. J., and Fanning, E. 1992, Interaction of DNA polymerase alpha-primase with cellular replication protein A and SV40 T antigen, EMBO J. 11:769–776.PubMedGoogle Scholar
  162. 162.
    Gannon, J. V., and Lane, D. P., 1987, p53 and DNA polymerase a compete for binding to SV40 T antigen, Nature 329:456–458.PubMedCrossRefGoogle Scholar
  163. 163.
    Zhu, J., Rice, P. W., Chamberlain, M., and Cole, C. N., 1991, Mapping the transcriptional transactivation function of simian virus 40 large T antigen, J. Virol. 65:2778–2790.PubMedGoogle Scholar
  164. 164.
    Gruda, M. C., Zabolotny J. M., Xiao J. H., Davidson, I., and Alwine J. C., 1993, Transcriptional activation by simian virus 40 large T antigen: Interactions with multiple components of the transcription complex, Mol. Cell. Biol. 13:961–969.PubMedGoogle Scholar
  165. 165.
    Bollag, B, Chuke, W. F., and Frisque, R. J., 1989, Hybrid genomes of the polyomaviruses JC virus, BK virus, and simian virus 40: Identification of sequences important for efficient transformation, J. Virol. 63:863–872.PubMedGoogle Scholar
  166. 166.
    Haggerty, S., Walker, D. L., and Frisque, R. J., 1989, JC virus-simian virus 40 genomes containing heterologous regulatory signals and chimeric early regions: Identification of regions restricting transformation by JC virus, J. Virol. 63:2180–2190.PubMedGoogle Scholar
  167. 167.
    Dyson, N., Bernards, R., Friend, S. H., Gooding, L. R., Hassell, J. A., Major, E. O., Pipas, J. M., Vandyke, T., and Harlow, E., 1990, Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein, J. Virol. 64:1353–1356.PubMedGoogle Scholar
  168. 168.
    Benjamin, T., and Vogt, P. K., 1991, Cell transformation by viruses, in: Fundamental Virology (B. N. Fields, D. M. Knipe, R. M. Chanock, M. S. Hirsch, J. L. Melnick, T. P. Monath, and B. Roizman, eds.), Raven Press, New York, pp. 321–325.Google Scholar
  169. 169.
    Freund, R., Sotnikov, A., Bronson, R. T., and Benjamin, T. L., 1992, Polyoma virus middle T is essential for virus replication and persistence as well as for tumor induction in mice, Virology 191:716–723.PubMedCrossRefGoogle Scholar
  170. 170.
    Resnick-Silverman, L., Pang, Z., Li, G., Jha, K. K., and Ozer, H. L., 1991, Retinoblastoma protein and simian virus 40-dependent immortalization of human fibroblasts, J. Virol. 65:2845–2852.PubMedGoogle Scholar
  171. 171.
    Freund, R., Bronson, R. T., and Benjamin, T. L., 1992, Separation of immortalization from tumor induction with polyoma large T mutants that fail to bind the retinoblastoma gene product, Oncogene 7:1979–1987.PubMedGoogle Scholar
  172. 172.
    Courtneidge, S. A., and Smith, A. E., 1983, Polyoma virus transforming protein associates with the product of the c-src cellular gene, Nature 303:435–439.PubMedCrossRefGoogle Scholar
  173. 173.
    Courtneidge, S. A., and Smith, A. E., 1984, The complex of polyoma virus middle-T antigen and pp60c-src, EMBO J. 3:585–591.PubMedGoogle Scholar
  174. 174.
    Kornbluth, S., Sudol, M., and Hanafusa, H., 1987, Association of the polyomavirus middle-T antigen with c-yes protein, Nature 325:171–173.PubMedCrossRefGoogle Scholar
  175. 175.
    Cheng, S. H., Harvey, R., Espino, P. C., Semba, K., Yamamoto, T., Toyoshima, K., and Smith, A. E., 1988, Peptide antibodies to the human c-fyn gene product demonstrate pp59c-fyn is capable of complex formation with middle-T antigen of polyomavirus, EMBO J. 7:3845–3855.PubMedGoogle Scholar
  176. 176.
    Horak, I. D., Kawakami, T., Gregory, F., Robbins, K. C., and Bolen, J. B., 1989, Association of p60fym with middle tumor antigen in murine polyomavirus-transformed rat cells, J. Virol. 63:2343–2347.PubMedGoogle Scholar
  177. 177.
    Kypta, R. M., Hemming, A., and Courtneidge, S. A., 1988, Identification and characterization of p59fyn (a src-like protein tyrosine kinase) in normal and polyomavirus transformed cells, EMBO J 7:3837–3844.PubMedGoogle Scholar
  178. 178.
    Courtneidge, S. A., 1985, Activation of the pp60c-src kinase by middle T antigen binding or by dephosphorylation, EMBO J. 4:1471–1477.PubMedGoogle Scholar
  179. 179.
    Bolen, J. B., Thiele, C. J., Israel, M. A., Yonemoto, W., Lipsich, L. A., and Brugge, J. S., 1984, Enhancement of cellular src gene product associated tyrosyl kinase activity following polyoma virus infection and transformation, Cell 38:767–777.PubMedCrossRefGoogle Scholar
  180. 180.
    Matthews, J. T., and Benjamin, T. L., 1986, 12-o-Tetradecanoylphorbol-13-acetate stimulates phosphorylation of the 58,000-Mr form of polyoma virus middle T antigen in vivo: Implications of a possible role of protein kinase C in middle T function, J. Virol. 58:239–246.PubMedGoogle Scholar
  181. 181.
    Harvey, R., Oostra, B. A., Belsham, G. J., Gillett, P., and Smith, A. E., 1984, An antibody to a synthetic peptide recognizes polyomavirus middle-T antigen and reveals multiple in vitro tyrosine phosphorylation sites, Mol. Cell. Biol. 4:1334–1342.PubMedGoogle Scholar
  182. 182.
    Hunter, T., Hutchinson, M. A., and Eckhart, W., 1984, Polyoma middle-sized T antigen can be phosphorylated on tyrosine at multiple sites in vitro, EMBO J. 3:73–79.PubMedGoogle Scholar
  183. 183.
    Schaffhausen, B., and Benjamin, T. L., 1981, Comparison of phosphorylation of two polyoma virus middle T antigens in vivo and in vitro, J. Virol. 40:184–196.PubMedGoogle Scholar
  184. 184.
    Talmage, D. A., Freund, R., Young, A. T., Dahl, J., Dawe, C. J., and Benjamin, T. L., 1989, Phosphorylation of middle T by pp60c-src: A switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis, Cell 59:55–65.PubMedCrossRefGoogle Scholar
  185. 185.
    Courtneidge, S. A., and Heber, A., 1987, An 81 kd protein complexed with middle T antigen and pp60c-src: A possible phosphatidylinositol kinase, Cell 50:1031–1037.PubMedCrossRefGoogle Scholar
  186. 186.
    Kaplan, D. R., Whitman, M., Schaffhausen, B., Pallas, D. C., White, M., and Cantley, L., 1987, Common elements in growth factor stimulation and oncogenic transformation: 85kd phos-phoprotein and phosphatidylinositol kinase activity, Cell 50:1021–1029.PubMedCrossRefGoogle Scholar
  187. 187.
    Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz-Larrea, F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N., Smith, A. D., Morgan, S. J., Courtneidge, S. A., Parker, P. J., and Waterfield, M. D., 1991, Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase, Cell 65:91–104.PubMedCrossRefGoogle Scholar
  188. 188.
    Whitman, M., Downes, C. P., Keeler, M., Keller, T., and Cantley, L., 1988, Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate, Nature 332:644–646.PubMedCrossRefGoogle Scholar
  189. 189.
    Pallas, D. C., Shahrik, L. K., Martin, B. L., Jaspers, S., Miller, T. B., Brautigan, D. L., and Roberts, T. M., 1990, Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A, Cell 60:167–176.PubMedCrossRefGoogle Scholar
  190. 190.
    Walter, G., Ruediger, R., Slaughter, C., and Mumby, M., 1990, Association of protein phosphatase 2A with polyoma virus medium tumor antigen, Proc. Natl Acad. Sci. USA 87:2521–2525.PubMedCrossRefGoogle Scholar
  191. 191.
    Rameh, L. E., and Armelin, M. C. S., 1991, T antigens’ role in polyomavirus transformation: c-myc but not c-fos or c-jun expression is a target for middle T, Oncogene 6:1049–1056.PubMedGoogle Scholar
  192. 192.
    Jalinek, M. A., and Hassell, J. A., 1992, Reversion of middle T antigen-transformed Rat-2 cells by Krev-1: Implications for the role of p21c-ras in polyomavirus-mediated transformation, Oncogene 7:1687–1698.Google Scholar
  193. 193.
    Feunteun, J., Kress, M., Gardes, M., and Monier, R., 1978, Viable deletion mutants in the simian virus 40 early region, Proc. Natl. Acad. Sci. USA 75:4455–4459.PubMedCrossRefGoogle Scholar
  194. 194.
    Martin, R. G., Setlow, V. P., Edwards, C. A. F., and Vembu, D., 1979, The roles of the simian virus 40 tumor antigens in transformation of Chinese hamster lung cells, Cell 17:635–643.PubMedCrossRefGoogle Scholar
  195. 195.
    Seif, R., and Martin, R. G., 1979, Simian virus 40 small t antigen is not required for the maintenance of transformation but may act as a promoter (cocarcinogen) during establishment of transformation in resting rat cells, J. Virol. 32:979–988.PubMedGoogle Scholar
  196. 196.
    Sleigh, M. J., Topp, W. C., Hanich, R., and Sambrook, J. F., 1978, Mutants of SV40 with an altered small t protein are reduced in their ability to transform cells, Cell 14:79–88.PubMedCrossRefGoogle Scholar
  197. 197.
    Bikel, I., Montano, X., Agha, M. E., Brown, M., McCormack, M., Boltax, J., and Livingston, D. M., 1987, SV40 small t antigen enhances the transformation activity of limiting concentrations of SV40 large T antigen, Cell 48:321–330.PubMedCrossRefGoogle Scholar
  198. 198.
    Loeken, M., Bikel, I., Livingston, D. M., and Brady, J., 1988, Trans-activation of RNA poly-merase II and III promoters by SV40 small t antigen, Cell 55:1171–1177.PubMedCrossRefGoogle Scholar
  199. 199.
    Graessmann, A., Graessmann, M., Tjian, R., and Topp, W. C., 1980, Simian virus 40 small-t protein is required for loss of actin cable networks in rat cells, J. Virol. 33:1182–1191.PubMedGoogle Scholar
  200. 200.
    Hiscott, J. B., and Defendi, V., 1981, Simian virus 40 gene A regulation of cellular DNA synthesis. II. In nonpermissive cells, J. Virol. 37:802–812.PubMedGoogle Scholar
  201. 201.
    Carbone, M., Hauser, J., Carty, M. P., Rundell, K., Dixon, K., and Levine, A. S., 1992, Simian virus 40 (SV40) small t antigen inhibits SV40 DNA replication in vitro J. Virol. 66:1804–1808.PubMedGoogle Scholar
  202. 202.
    Scheidtmann, K. H., Mumby, M. C., Rundell, K., and Walter, G., 1991, Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phophatase 2A: Inhibition by small-t antigen, Mol. Cell. Biol 11:1996–2003.PubMedGoogle Scholar
  203. 203.
    Sontag, E., Federov, S., Kamibayashi, C., Robbins, D., Cobb, M., and Mumby, M., 1993, The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the MAP kinase pathway and induces cell proliferation, Cell 75:887–897.PubMedCrossRefGoogle Scholar
  204. 204.
    Yang, S., Lickteig, R. L., Estes, R., Rundell, K., Walter, G., and Mumby, M., 1991, Control of protein phosphatase 2A by simian virus 40 small-t antigen, Mol. Cell. Biol. 11:1988–1995.PubMedGoogle Scholar
  205. 205.
    Wheat, W. H., Roesler, W. J., and Klemm, D. J., 1994, Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation, Mol Cell. Biol. 14:5881–5890.PubMedCrossRefGoogle Scholar
  206. 206.
    Ogryzko, V. V., Hirai, T. H., Shih, C. E., and Howard, B. H., 1994, Dissociation of retino-blastoma gene protein hyperphosphorylation and commitment to enter S phase, J. Virol 68:3724–3732.PubMedGoogle Scholar
  207. 207.
    Dobbelstein, M., Arthur, A. K., Dehde, S., van-Zee, K., Dickmanns, A., and Fanning, E., 1992, Intracistronic complementation reveals a new function of SV40 T antigen that co-operates with Rb and p53 binding to stimulate DNA synthesis in quiescent cells, Oncogene 7:837–847.PubMedGoogle Scholar
  208. 208.
    Maclean, K., Rogan, E. M., Whitaker, N.J., Chang, A. C., Rowe, P. B., Dalla-Pozza, L., Symonds, G., and Reddel, R. R., 1994, In vitro transformation of Li-Fraumeni syndrome fibroblasts by SV40 large T antigen mutants, Oncogene 9:719–725.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Daniel T. Simmons
    • 1
  1. 1.Department of BiologyUniversity of DelawareNewarkUSA

Personalised recommendations