Journal of Physiology and Biochemistry

, Volume 60, Issue 4, pp 287–307 | Cite as

p53: Twenty five years understanding the mechanism of genome protection

  • M. Gomez-Lazaro
  • F. J. Fernandez-Gomez
  • J. Jordán


This year the p53 protein, also known as “guardian of the genome”, turns twenty five years old. During this period the p53 knowledge have changed from an initial pro-oncogene activity to the tumorsupressor p53 function. p53 is activated upon stress signals, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading to protection of cells by inducing target genes. The molecules activated by p53 induce cell cycle arrest, DNA repair to conserve the genome and apoptosis. The regulation of p53 functions is tightly controlled through several mechanisms including p53 transcription and translation, protein stability, post-translational modifications, and subcellular localization. In fact, mutations in p53 are the most frequent molecular alterations detected in human tumours. Furthermore, in some degenerative processes, fragmentation and oxidative damage in DNA take place, and in these situations p53 is involved. So, p53 is considered a pharmacological target, p53 overexpression induces apoptosis in cancer and its expression blockage protects cells against lethal insults.

Key words

Apoptosis Necrosis mdm2 Cancer Tumor suppressor Mutation 


Apoptosis Necrosis mdm2 Cáncer Supresor tumoral Mutación 


En este año, la proteína p53, también conocida como “el guardián del genoma”, cumple veinticinco años. Durante este periodo, el conocimiento sobre las funciones desempeñadas por p53 ha ido cambiando desde una actividad pro-oncogénica hasta su función oncosupresora. Esta proteína se activa en respuesta a estímulos de estrés como radiaciones gamma y ultravioleta, hipoxia, infección vírica y daño en el ADN, protegiendo a la célula mediante acción sobre sus genes diana. Las moléculas activadas por p53 inducen parada en ciclo celular y reparación del ADN con el fin de conservar el genoma o de inducir apoptosis. La regulación de las funciones de p53 está controlada estrechamente a través de varios mecanismos que incluyen la transcripción, traducción, estabilidad de la proteína por modificaciones posttranscripcionales y su localización subcelular. Una de las alteraciones moleculares detectadas con más frecuencia en los tumores humanos son las mutaciones en p53. Mas aún, en algunos procesos degenerativos, donde tiene lugar la fragmentación y el daño oxidativo en el ADN, la p53 está implicada. Así, se considera a la p53 como una posible diana farmacológica, ya que su sobreexpresión induce apoptosis en células cancerosas y el bloqueo de su expresión protege a las células contra daños letales.


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  1. 1.
    Aas, T., Borresen, A. L., Geisler, S., Smith-Sorensen, B., Johnsen, H., Varhaug, J. E., Akslen, L. A. and Lonning, P. E. (1996):Nat. Med.,2, 811–814.PubMedCrossRefGoogle Scholar
  2. 2.
    Alves Da Costa, C., Paitel, E., Vincent, B. and Checler, F. (2002):J. Biol. Chem.,277, 50980–50984.PubMedCrossRefGoogle Scholar
  3. 3.
    Armstrong, J. F., Kaufman, M. H. Harrison, D. J. and Clarke, A. R. (1995):Curr. Biol.,8, 937–943.Google Scholar
  4. 4.
    Ashkenazi, A. and Dixitm, V. M. (1998):Science,281, 1305–1308.PubMedCrossRefGoogle Scholar
  5. 5.
    Avantaggiati, M. L., Ogryzko, V., Gardner, K., Giordano, A., Levine, A. S. and Kelly, K. (1997):Cell,89, 1175–1184.PubMedCrossRefGoogle Scholar
  6. 6.
    Baker, S. J., Fearon, E. R., Nigro, J. M., Hamilton, S. R., Preisinger, A. C., Jessup, J. M., van Tuinen, P., Ledbetter, D. H., Barker, D. F., Nakamura, al. (1989):Science,244, 217–221.PubMedCrossRefGoogle Scholar
  7. 7.
    Barak, Y., Juven, T., Haffner, R. and Oren, M. (1993):EMBO J.,12, 461–468.PubMedGoogle Scholar
  8. 8.
    Bayle, J. H., Elenbaas, B. and Levine, A. J. (1995):Proc. Natl. Acad. Sci. USA,92, 5729–5733.PubMedCrossRefGoogle Scholar
  9. 9.
    Bech-Otschir, D., Kraft, R., Huang, X., Henklein, P., Kapelari, B., Pollmann, C. and Dubiel, W. (2001):EMBO J.,20, 1630–1639.PubMedCrossRefGoogle Scholar
  10. 10.
    Bennett, M. R., Evan, G. I. and Schwartz, S. M. (1995):Circ. Res.,77, 266–273.PubMedGoogle Scholar
  11. 11.
    Bennett, M. R., Littlewood, T. D., Schwartz, S. M. and Weissberg, P. L. (1997):Circ. Res.,81, 591–599.PubMedGoogle Scholar
  12. 12.
    Bergamaschi, D., Samuels, Y., Jin, B., Duraisingham, S., Crook, T. and Lu, X. (2004):Mol. Cell Biol.,24, 1341–1350.PubMedCrossRefGoogle Scholar
  13. 13.
    Brachmann, R. K., Yu, K., Eby, Y., Pavletich, N. P. and Boeke, J. D. (1998):EMBO J.,17, 1847–1859.PubMedCrossRefGoogle Scholar
  14. 14.
    Braithwaite, A. W., Blair, G. E., Nelson, C. C., McGovern, J. and Bellett, A. J. (1991):Oncogene,6, 781–787.PubMedGoogle Scholar
  15. 15.
    Burch, L. R., Midgley, C. A., Currie, R. A., Lane, D. P. and Hupp, T. R. (2000):FEBS Lett.,472, 93–98.PubMedCrossRefGoogle Scholar
  16. 16.
    Caelles, C., Helmberg, A. and Karin, M. (1994):Nature,370, 220–223.PubMedCrossRefGoogle Scholar
  17. 17.
    Calmels, S., Hainaut, P. and Ohshima, H. (1997):Cancer Res.,57, 3365–3369.PubMedGoogle Scholar
  18. 18.
    Campisi, J. (2000):In Vivo,14, 183–188.PubMedGoogle Scholar
  19. 19.
    Campomenosi, P., Monti, P., Aprile, A., Abbondandolo, A., Frebourg, T., Gold, B., Crook, T., Inga, A., Resnick, M. A., Iggo, R. and Fronza, G. (2001)Oncogene,20, 3573–3579PubMedCrossRefGoogle Scholar
  20. 20.
    Caron de Fromentel, C., May-Levin, F., Mouriesse, H., Lemerle, J., Chandrasekaran, K. and May, P. (1987):Int. J. Cancer,39, 185–189.PubMedCrossRefGoogle Scholar
  21. 21.
    Chang, C., Simmons, D. T., Martin, M. A. and Mora, P. T. (1979):J Virol.,31, 463–471.PubMedGoogle Scholar
  22. 22.
    Chen, L. and Chen, J. (2003):Oncogene,22, 5348–5357.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen, R. W. and Chuang, D. M. (1999):J. Biol. Chem.,274, 6039–6042.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen, X., Farmer, G., Zhu, H., Prywes, R. and Prives, C. (1993):Genes Dev. 7, 1837–1849 Erratum in: (1993):Genes Dev.,7(12B), 2652.PubMedCrossRefGoogle Scholar
  25. 25.
    Cho, Y., Gorina, S., Jeffrey, P. D. and Pavletich, N. P. (1994):Science,265, 345–355.CrossRefGoogle Scholar
  26. 26.
    Clayman, G. L., el-Naggar, A. K., Lippman, S. M., Henderson, Y. C., Frederick, M., Merritt, J. A., Zumstein, L. A., Timmons, T. M., Liu, T. J., Ginsberg, L., Roth, J. A., Hong, W. K., Bruso, P. and Goepfert, H. (1998):J. Clin. Oncol.,16, 2221–2232.PubMedGoogle Scholar
  27. 27.
    Craig, A. L., Blaydes, J. P., Burch, L. R., Thompson, A. M. and Hupp, T. R. (1999):Oncogene,18, 6305–6312.PubMedCrossRefGoogle Scholar
  28. 28.
    Craig, A. L., Burch, L., Vojtesek, B., Mikutowska, J., Thompson, A., and Hupp, T. R. (1999):Biochem. J.,342, 133–141.PubMedCrossRefGoogle Scholar
  29. 29.
    Crawford, L. V., Pim, D. C. and Bulbrook, R. D. (1982):Int. J. Cancer,30, 403–408.PubMedCrossRefGoogle Scholar
  30. 30.
    Da Costa C. A., Masliah, E. and Checler, F. (2003):J. Biol. Chem.,278, 37330–37335.PubMedCrossRefGoogle Scholar
  31. 31.
    De la Monte, S. M., Sohn, Y. K. and Wands, J. R. (1997):J. Neurol. Sci.,152, 73–83.PubMedCrossRefGoogle Scholar
  32. 32.
    De Leo, A. B., Jay, G., Appella, E., Dubois, G. C., Law, L. W. and Old, L. J. (1979):Proc. Natl. Acad. Sci. USA,76, 2420–2424.CrossRefGoogle Scholar
  33. 33.
    Delphin, C., Cahen, P., Lawrence, J. J. and Baudier, J. (1994):Eur. J. Biochem.,223, 683–692.PubMedCrossRefGoogle Scholar
  34. 34.
    Dewson, G., Cohen, G. M. and Wardlaw, A. J. (2001):Blood,98, 2239–2247.PubMedCrossRefGoogle Scholar
  35. 35.
    Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A. Jr., Butel, J. S. and Bradley, A. (1992):Nature,356, 215–221.PubMedCrossRefGoogle Scholar
  36. 36.
    Dornan, D. and Hupp, T. R. (2001):EMBO Rep.,2, 139–144.PubMedCrossRefGoogle Scholar
  37. 37.
    Dornan, D., Bheddah, S., Newton, K., Ince, W., Frantz, G. D., Dowd, P., Koeppen, H., Dixit, V. M. and French, D. M. (2004):Cancer Res.,64, 7226–7230.PubMedCrossRefGoogle Scholar
  38. 38.
    Duan, W., Zhu, X., Ladenheim, B., Yu, Q. S., Guo, Z., Oyler, J., Cutler, R. G., Cadet, J. L., Greig, N. H. and Mattson, M. P. (2002):Ann. Neurol.,52, 597–606.PubMedCrossRefGoogle Scholar
  39. 39.
    Dumaz, N. and Meek, D. W. (1999):EMBO J.,18, 7002–7010.PubMedCrossRefGoogle Scholar
  40. 40.
    Dutta, A., Ruppert, J. M., Aster, J. C. and Winchester, E. (1993):Nature,365, 79–82.PubMedCrossRefGoogle Scholar
  41. 41.
    El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Maercer, W. E., Kinzler, K. W. and Vogelstein, B. (1993):Cell,75, 817–825.PubMedCrossRefGoogle Scholar
  42. 42.
    El-Deiry, W.S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. and Vogelstein, B. (1992):Nat. Genet.,1, 45–49.PubMedCrossRefGoogle Scholar
  43. 43.
    Eliyahu, D., Raz, A., Gruss, P., Givol, D. and Oren, M. (1984):Nature,312, 646–649.PubMedCrossRefGoogle Scholar
  44. 44.
    Fields, S. and Jang, S. K. (1990):Science,249, 1046–1049.PubMedCrossRefGoogle Scholar
  45. 45.
    Finlay, C. A., Hinds, P. W. and Levine, A. J. (1989):Cell,57, 1083–1093.PubMedCrossRefGoogle Scholar
  46. 46.
    Finlay, C. A., Hinds, P. W., Tan, T. H., Eliyahu, D., Oren, M. and Levine, A. J. (1988):Mol. Cell Biol.,2, 531–539.Google Scholar
  47. 47.
    Forrester, K., Ambs, S., Lupold, S. E., Kapust, R. B., Spillare, E. A., Weinberg, W. C., Felley-Bosco, E., Wang, X. W., Geller, D. A., Tzeng, E., Billiar, T. R., and Harris, C. C. (1996):Proc. Natl. Acad. Sci. U S A,93, 2442–2447.PubMedCrossRefGoogle Scholar
  48. 48.
    Geisler, S., Lonning, P. E., Aas, T., Johnsen, H., Fluge, O., Haugen, D. F., Lillehaug, J. R., Akslen, L. A. and Borresen-Dale, A. L. (2001):Cancer Res.,61, 2505–2512.PubMedGoogle Scholar
  49. 49.
    Giaccia, A. J. and Kastan, M. B. (1999):Genes Dev.,12, 2973–2983.CrossRefGoogle Scholar
  50. 50.
    Giasson, B. I., Ischiropoulos, H., Lee, V. M. and Trojanowski, J. Q. (2002):Free Radic. Biol. Med.,32, 1264–1275.PubMedCrossRefGoogle Scholar
  51. 51.
    Gottifredi, V., McKinney, K., Poyurovsky, M. V. and Prives, C. (2004):J. Biol. Chem.,279, 5802–5810.PubMedCrossRefGoogle Scholar
  52. 52.
    Gottlieb, T. M. and Oren, M. (1996):Biochem. Biophys. Acta,1287, 77–102.PubMedGoogle Scholar
  53. 53.
    Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W. and Giaccia, A. J. (1996):Nature,379, 88–91.PubMedCrossRefGoogle Scholar
  54. 54.
    Gu, W., Luo, J., Brooks, C. L., Nikolaev, A. Y. and Li, M. (2004):Novartis Found Symp.,259, 197–205.PubMedCrossRefGoogle Scholar
  55. 55.
    Guevara, N. V., Kim, H. S., Antonova, E. I. and Chan, L. (1999):Nat. Med.,5, 335–339.PubMedCrossRefGoogle Scholar
  56. 56.
    Hainaut, P. and Milner, J. (1993):Cancer Res.,53, 1739–1742.PubMedGoogle Scholar
  57. 57.
    Harada, H., Becknell, B., Wilm, M., Mann, M., Huang, L. J., Taylor, S. S., Scott J. D. and Korsmeyer, S. J. (1999):Mol Cell.,3, 413–422.PubMedCrossRefGoogle Scholar
  58. 58.
    Haupt, Y., Barak, Y. and Oren, M. (1996):EMBO J.,15, 1596–1606.PubMedGoogle Scholar
  59. 59.
    Hinds, P., Finlay, C. and Levine, A. J. (1989):J. Virol,63, 739–746.PubMedGoogle Scholar
  60. 60.
    Hirata, H. and Cadet, J. L. (1997):J. Neurochem.,69, 780–790.PubMedGoogle Scholar
  61. 61.
    Hollstein, M., Rice, K., Greenblatt, M. S., Soussi, T., Fuchs, R., Sorlie, T., Hovig, E., Smith-Sorensen, B., Montesano, R. and Harris, C. C. (1994),Nucleic Acids Res.,22, 3551–3555.PubMedGoogle Scholar
  62. 62.
    Honda, R., Tanaka, H. and Yasuda, H. (1997):FEBS Lett.,420, 25–27.PubMedCrossRefGoogle Scholar
  63. 63. Scholar
  64. 64.
    Irwin, M. S. and Kaelin, W. G. Jr. (2001):Apoptosis,6, 17–29.PubMedCrossRefGoogle Scholar
  65. 65.
    Itahana, K., Dimri, G. P., Hara, E., Itahana, Y., Zou, Y., Desprez, P. Y. and Campisi, J. (2002):J. Biol. Chem.,277, 18206–18214.PubMedCrossRefGoogle Scholar
  66. 66.
    Ito, A., Kawaguchi, Y., Lai, C. H., Kovacs, J. J., Higashimoto, Y., Appella, E. and Yao, T. P. (2002):EMBO J.,21, 6236–6245.PubMedCrossRefGoogle Scholar
  67. 67.
    Iwakuma, T. and Lozano, G. (2003):Mol. Cancer Res.,1, 993–1000.PubMedGoogle Scholar
  68. 68.
    Jayaraman, L., Moorthy, N. C., Murthy, K. G., Manley, J. L., Bustin, M. and Prives, C. (1998):Genes Dev.,12, 462–472.PubMedCrossRefGoogle Scholar
  69. 69.
    Jeffers, J. R., Parganas, E., Lee, Y., Yang, C., Wang, J., Brennan, J., MacLean, K. H., Han, J., Chittenden, T., Ihle, J. N., McKinnon, P. J., Cleveland, L. and Zambetti, G. P. (2003):Cancer Cell,4, 321–328.PubMedCrossRefGoogle Scholar
  70. 70.
    Jia, L., Patwari, Y., Srinivasula, S. M., Newland, A. C., Fernandes-Alnemri, T., Alnemri, E. S. ans Kelsey, S. M. (2001):Oncogene,20, 4817–4826.PubMedCrossRefGoogle Scholar
  71. 71.
    Johnson, T. M., Yu., Z. X., Ferrans, V. J., Lowenstein, R. A. and Finkel, T. (1996)Proc. Natl. Acad. Sci. U. S. A. 93, 11848–11852.PubMedCrossRefGoogle Scholar
  72. 72.
    Jones, S. N., Roe, A. E., Donehower, L. A. and Bradley, A. (1995):Nature,378, 206–208.PubMedCrossRefGoogle Scholar
  73. 73.
    Joo, C. K., Choi, J. S., Ko, H. W., Park, K. Y., Sohn, S., Chun, M. H., Oh, Y. J. and Gwag, B. J. (1999):Invest. Ophthalmol. Vis. Sci.,40, 713–720.PubMedGoogle Scholar
  74. 74.
    Jordan, J., Galindo, M. F., Gonzalez-Garcia, C. and Cena, V. (2003):Neurocience,122, 707–715.CrossRefGoogle Scholar
  75. 75.
    Kaghad, M., Bonnet, H., Yang, A., Creancier, L., Biscan, J. C., Valent, A., Minty, A., Chalon, P., Lelias, J. M., Dumont, X., Ferrara, P., McKeon, F. and Caput, D. (1997):Cell,90, 809–819.PubMedCrossRefGoogle Scholar
  76. 76.
    Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. and Craig, R. W. (1991):Cancer Res.,51, 6304–6311.PubMedGoogle Scholar
  77. 77.
    Kern, S. E., Kinzler, K. W., Bruskin, A., Jarosz, D., Friendman, P., Prives, C. and Vogelstein, B. (1991):Science,252, 1708–1711.PubMedCrossRefGoogle Scholar
  78. 78.
    Kinscherf, R., Deigner, H. P., Usinger, C., Pill, J., Wagner, M., Kamencic, H., Hou, D., Chen, M., Schmiedt, W., Schrader, M., Kovacs, G., Kato, K. and Metz, J. (1997):FASEB J.,11, 1317–1328.PubMedGoogle Scholar
  79. 79.
    Kitamura, Y., Shimohama, S., Kamoshima, W., Matsuoka, Y., Nomura, Y. and Taniguchi, T. (1997):Biochem. Biophys. Res. Commun.,232, 418–421.PubMedCrossRefGoogle Scholar
  80. 80.
    Komarov, P. G., Komarova, E. A., Kondratov, R. V., Christov-Tselkov, K., Coon, J. S., Chernov, M. V. and Gudkov, A. V. (1999):Science,285, 1733–1737.PubMedCrossRefGoogle Scholar
  81. 81.
    Komarova, E. A., Zelnick, C. R., Chin, D., Zeremski, M., Gleiberman, A. S., Bacus, S. S. And Gudkov, A. V. (1997):Cancer Res.,57, 5217–5220.PubMedGoogle Scholar
  82. 82.
    Kress, M., May E., Cassingena, R. and May, P. (1979):J. Virol.,31, 472–483.PubMedGoogle Scholar
  83. 83.
    Kubbutat, M. H. and Vousden, K. H. (1997):Mol. Cell Biol.,17, 460–468.PubMedGoogle Scholar
  84. 84.
    Lakkaraju, A., Dubinsky, J. M., Low, W. C. and Rahman, Y. E. (2001):J. Biol. Chem.,276, 32000–32007.PubMedCrossRefGoogle Scholar
  85. 85.
    Lambert, P. F., Kashanchi, F., Radonovich, M. F., Shiekhattar, R. and Brady, J. N. (1998):J. Biol. Chem. 273, 33048–33053.PubMedCrossRefGoogle Scholar
  86. 86.
    Lane, D. P. (1992):Nature,358, 15–16.PubMedCrossRefGoogle Scholar
  87. 87.
    Lane, D. P. and Crawford, L. V. (1979):Nature,278, 261–263.PubMedCrossRefGoogle Scholar
  88. 88.
    Levine, A. J. (1997):Cell,88, 323–331.PubMedCrossRefGoogle Scholar
  89. 89.
    Levrero, M., De Laurenzi, V., Costanzo, A., Gong, J., Wang, J. Y. and Melino, G. (2000):J. Cell Sci.,113, 1661–1670.PubMedGoogle Scholar
  90. 90.
    Li, J. H., Lax, S. A., Kim, J., Klamut, H. and Liu, F. F. (1999):Int. J. Radiat. Oncol. Biol. Phys.,43, 607–616.PubMedGoogle Scholar
  91. 91.
    Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J. and Gu, W. (2002):Nature,416, 648–653.PubMedCrossRefGoogle Scholar
  92. 92.
    Li, P. F., Dietz, R. and von Harsdorf, R. (1999):EMBO J.,18, 6027–6036.PubMedCrossRefGoogle Scholar
  93. 93.
    Lin, Y., Ma, W. and Benchimol, S. (2000):Nature Genetics,26, 122–127.PubMedCrossRefGoogle Scholar
  94. 94.
    Linke, S. P., Clarkin, K. C., Di Leonardo, A., Tsou, A. and Wahl, G. M. (1996):Genes Dev.,10, 934–947.PubMedCrossRefGoogle Scholar
  95. 95.
    Linzer, D. I. H. and Levine, A. J. (1979):Cell,1, 43–52.CrossRefGoogle Scholar
  96. 96.
    Lu, H. and Levine, A. J. (1995):Proc. Natl. Acad. Sci. USA,92, 5154–5158.PubMedCrossRefGoogle Scholar
  97. 97.
    Lu, H., Fisher, R. P., Bailey, P. and Levine, A. J. (1997):Mol. Cell Biol.,17, 5923–5934.PubMedGoogle Scholar
  98. 98.
    Mai, M., Huang, H., Reed, C., Qian, C., Smith, J. S., Alderete, B., Jenkins, R., Smith, D. I. and Liu, W. (1998):Genomics,51, 359–363.PubMedCrossRefGoogle Scholar
  99. 99.
    Maki, C. G. (1999):J. Biol. Chem.,274, 16531–16535.PubMedCrossRefGoogle Scholar
  100. 100.
    Maki, C. G., Huibregtse, J. M. and Howley, P. M. (1996):Cancer Res.,56, 2649–2654.PubMedGoogle Scholar
  101. 101.
    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. al. (1990):Science,250, 1233–1238. Erratum in: (1993):Science,259, 878.PubMedCrossRefGoogle Scholar
  102. 102.
    Maltzman, W. and Czyzyk, L. (1984):Mol. Cell Biol.,4, 1689–1694.PubMedGoogle Scholar
  103. 103.
    Mandir, A. S., Simbulan-Rosenthal, C. M., Poitras, M. F., Lumpkin, J. R., Dawson, V. L., Smulson, M. E. and Dawson T. M. (2002):J. Neurochem.,83, 186–192.PubMedCrossRefGoogle Scholar
  104. 104.
    Marchenko, N. D., Zaika, A. and Moll, U. M. (2000):J. Biol. Chem.,275, 16202–16212.PubMedCrossRefGoogle Scholar
  105. 105.
    Marin, M. C., Jost, C. A., Irwin, M. S., DeCaprio, J. A., Caput, D. and Kaelin, W. G. Jr. (1998):Mol. Cell Biol.,18, 6316–6324.PubMedGoogle Scholar
  106. 106.
    Martin, L. J. (2000):Neurobiol. Dis.,7, 613–622.PubMedCrossRefGoogle Scholar
  107. 107.
    Martinet, W., Knaapen, M. W., De Meyer, G. R., Herman, A. G. and Kockx, M. M. (20002):Circulation,106, 927–932.CrossRefGoogle Scholar
  108. 108.
    Melero, J. A., Stitt, D. T., Mangel, W. F. and Carrroll, R. B. (1979):J. Virol.,93, 466–480.CrossRefGoogle Scholar
  109. 109.
    Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P. and Moll, U. M. (2003):Mol. Cell.,11, 577–590.PubMedCrossRefGoogle Scholar
  110. 110.
    Mihara, M. and Moll, U. M. (2003):Methods Mol. Biol.,234, 203–209.PubMedGoogle Scholar
  111. 111.
    Milne, D. M., McKendrick, L., Jardine, L. J., Deacon, E., Lord, J. M. and Meek. D. W. (1996):Oncogene,13, 205–211.PubMedGoogle Scholar
  112. 112.
    Morrison, R. S., Wenzel, H. J., Kinoshita, Y., Robbins, C. A., Donehower, L. A. and Schwartzkroin, P. A. (1996):J. Neurosci.,16, 1337–1345.PubMedGoogle Scholar
  113. 113.
    Nakai, M., Qin, Z. H., Wang, Y. and Chase, T. N. (1999):Brain Res. Mol. Brain Res.,64, 59–68.PubMedCrossRefGoogle Scholar
  114. 114.
    Nakano, K. and Vousden, K. H. (2001):Mol. Cell,7, 683–694.PubMedCrossRefGoogle Scholar
  115. 115.
    Neuchushtan, A., Smith, C. L., Lamensdorf, I., Yoon, S. H. and Youle, R. J. (2001):J. Cell. Biol.,153, 1265–1276.CrossRefGoogle Scholar
  116. 116.
    Nicol, C. J., Harrison, M. L., Laposa, R. R., Gimelshtein, I. L. and Wells, P. G. (1995):Nat. Genet.,10, 181–187.PubMedCrossRefGoogle Scholar
  117. 117.
    Nikolaev, A. Y., Li, M., Puskas, N., Qin, J. and Gu, W. (2003):Cell,112, 29–40.PubMedCrossRefGoogle Scholar
  118. 118.
    Nikolova, P. V., Wong, K. B., DeDecker, B., Henckel, J. and Fersht, A. R. (2000):EMBO J.:19, 370–378.PubMedCrossRefGoogle Scholar
  119. 119.
    Ohnishi, T., Wang, X., Ohnishi, K., Matsumoto, H. and Takahashi, A. (1996):J. Biol. Chem.,271, 14510–14513.PubMedCrossRefGoogle Scholar
  120. 120.
    Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W. and Vogelstein, B. (1993):Nature,362, 857–860.PubMedCrossRefGoogle Scholar
  121. 121.
    Ollmann, M., Young, L. M., Di Como, C. J., Karim, F., Belvin, M., Robertson, S., Whittaker, K., Demsky, M., Fisher, W. W., Buchman, A., Duyk, G., Friedman, L., Prives, C. and Kopczynski, C. (2000):Cell,101, 91–101.PubMedCrossRefGoogle Scholar
  122. 122.
    Oren, M. (1999):J. Biol. Chem.,274, 36031–36034.PubMedCrossRefGoogle Scholar
  123. 123.
    Oren, M., Maltzman, W. and Levine, A. J. (1981):Mol. Cell Biol.,1, 101–110.PubMedGoogle Scholar
  124. 124.
    Owen-Schaub, L. B., Zhang, W., Cusack, J. C., Angelo, L. S., Santee, S. M., Fujiwara, T., Roth, J. A., Deisseroth, A. B., Zhang, W. W., Kruzel, al. (1995):Mol. Cell Biol.,15, 3032–3040.PubMedGoogle Scholar
  125. 125.
    Parada, L. F., Land, H., Weinberg, R. A., Wolf, D. and Rotter, V. (1984):Nature,312, 649–651.PubMedCrossRefGoogle Scholar
  126. 126.
    Pearson, G. D. and Merrill, G. F. (1998):J. Biol. Chem.,273, 5431–5434.PubMedCrossRefGoogle Scholar
  127. 127.
    Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W. and Vogelstein, B. (1997):Nature,389, 300–305.PubMedCrossRefGoogle Scholar
  128. 128.
    Price, B. D. and Calderwood, S. K. (1993):Oncogene,8, 3055–3062.PubMedGoogle Scholar
  129. 129.
    Reich, N. C. and Levine, A. J. (1984):Nature,308, 199–201.PubMedCrossRefGoogle Scholar
  130. 130.
    Rodrigues, N. R., Rowan, A., Smith, M. E., Kerr, I. B., Bodmer, W. F., Gannon, J. V. and Lane, D. P. (1990):Proc. Natl. Acad Sci. USA.,87, 7555–7559.PubMedCrossRefGoogle Scholar
  131. 131.
    Rogel, A., Popliker, M., Webb, C. G. and Oren, M. (1985):Mol. Cell Biol.,5, 2851–2855.PubMedGoogle Scholar
  132. 132.
    Rotter, V., Witte, O. N., Coffman, R. and Baltimore, D. (1980):J. Virol.,36, 547–555.PubMedGoogle Scholar
  133. 133.
    Sakaguchi, K., Saito, S., Higashimoto, Y., Roy, S., Anderson, C. W. and Appella, E. (2000):J. Biol. Chem.,275, 9278–9283.PubMedCrossRefGoogle Scholar
  134. 134.
    Samuels-Lev, Y., O’Connor, D. J., Bergamaschi, D., Trigiante, G., Hsieh, J. K., Zhong, S., Campargue, I., Naumovski, L., Crook, T. and Lu, X. (2001):Mol. Cell,8, 781–794.PubMedCrossRefGoogle Scholar
  135. 135.
    Seo, Y. R., Kelley, M. R. and Smith, M. L. (2002):Proc. Natl. Acad. Sci. USA,99, 14548–14553.PubMedCrossRefGoogle Scholar
  136. 136.
    Shaw, P., Bovey, R., Tardy, S., Sahli, R., Sordat, R. and Costa, J. (1992):Proc. Natl. Acad. Sci. USA.,89, 4495–4499.PubMedCrossRefGoogle Scholar
  137. 137.
    Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. and Prives, C. (2000):14, 289–300. Erratum in: (2000):Genes Dev.,14, 750.Google Scholar
  138. 138.
    Shieh, S. Y., Ikeda, M., Taya, Y. and Prives, C. (1997):Cell,91, 325–334.PubMedCrossRefGoogle Scholar
  139. 139.
    Sidransky, D., Mikkelsen, T., Schwechheimer, K., Rosenblum, M. L., Cavanee, W. and Vogelstein, B. (1992):Nature,355, 846–847.PubMedCrossRefGoogle Scholar
  140. 140.
    Sigal, A. and Rotter, V. (2000):Cancer Res.,60, 6788–6793.PubMedGoogle Scholar
  141. 141.
    Smith, M. L., Lancia, J. K. and Mercer, T. (2004):Anticancer Res.,24, 1401–1408.PubMedGoogle Scholar
  142. 142.
    Srivastava, S., Zou, Z. Q., Pirollo, K., Blattner, W. and Chang, E. H. (1990):Nature,348, 747–749.PubMedCrossRefGoogle Scholar
  143. 143.
    Stoll, R., Renner, C., Hansen, S., Palme, S., Klein, C., Belling, A., Zeslawski, W., Kamionka, M., Rehm, T., Muhlhahn, P., Schumacher, R., Hesse, F., Kaluza, B., Voelter, W., Engh, R. A. and Holak, T. A. (2001):Biochemistry,40, 336–344.PubMedCrossRefGoogle Scholar
  144. 144.
    Su, J. H., Anderson, A. J., Cummings, B. J. and Cotman, C. W. (1994):Neuroreport.,5, 2529–2533.PubMedGoogle Scholar
  145. 145.
    Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y. and Nakamura, Y. (2000):Nature,404, 42–49.PubMedCrossRefGoogle Scholar
  146. 146.
    Tao, W. and Levine, A. J. (1999):Proc. Natl. Acad. Sci USA,96, 3077–3080.PubMedCrossRefGoogle Scholar
  147. 147.
    Thornborrow, E. C., Patel, S., Mastropietro, A. E., Schwartzfarb, E. M. and Manfredi, J. J. (2002):Oncogene,21, 990–999.PubMedCrossRefGoogle Scholar
  148. 148.
    Trimmer, P. A., Smith, T. S., Jung, A. B. and Bennett, J. P. Jr. (1996):Neurodegeneration,5, 233–239.PubMedCrossRefGoogle Scholar
  149. 149.
    Uberti, D., Ferrari, Toninelli, G. and Memo, M. (2003):Toxicol. Lett.,139, 99–105.PubMedCrossRefGoogle Scholar
  150. 150.
    Uberti, D., Grilli, M. and Memo, M. (2000):Int. J. Dev. Neurosci.,18, 447–454.PubMedCrossRefGoogle Scholar
  151. 151.
    Unger, T., Sionov, R. V., Moallem, E., Yee, C. L., Howley, P. M., Oren, M. and Haupt, Y. (1999):Oncogene,18, 3205–3212.PubMedCrossRefGoogle Scholar
  152. 152.
    Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N. and Liu, E. A. (2004):Science,303, 844–848.PubMedCrossRefGoogle Scholar
  153. 153.
    Velez-Pardo, C., Ospina, G. G. and Jimenz del Rio, M. (2002):Neurotoxicology,23, 351–365.PubMedCrossRefGoogle Scholar
  154. 154.
    Venot, C., Maratrat, M., Dureuil, C., Conseiller, E., Bracco, L. and Debussche, L. (1998):EMBO J. 17, 4668–4679.PubMedCrossRefGoogle Scholar
  155. 155.
    Verhaegh, G. W., Richard, J. and Hainaut, P. (1997):Mol. Cell. Biol.,17, 5699–5706.PubMedGoogle Scholar
  156. 156.
    Vogelstein, B. and Kinzler, K. W. (1994):Nature,408, 307–310.CrossRefGoogle Scholar
  157. 157.
    Vogelstein, B., Lane, D. and Levine, A. J. (2000):Nature,408, 307–310.PubMedCrossRefGoogle Scholar
  158. 158.
    Walker, D., Bond, J., Tarone, R., Harris, C., Makalowski, W., Boguski, M. and Greenblatt, M. (1999):Oncognene,18, 211–218.CrossRefGoogle Scholar
  159. 159.
    Wang, X., Taplick, J., Geva, N. and Oren, M. (2004):FEBS Lett.,561, 195–201.PubMedCrossRefGoogle Scholar
  160. 160.
    Weber, J. D., Taylor, L. J., Rousssel, M. F., Sherr, C. J. and Bar-Sagi, D. (1999):Nat. Cell Biol.,1, 20–26.PubMedCrossRefGoogle Scholar
  161. 161.
    Webley, K., Bond, J. A., Jones, C. J., Blaydes, J. P., Craig, A., Hupp, T. and Wynford-Thomas, D. (2000):Mol. Cell Biol.,20, 2803–2808.PubMedCrossRefGoogle Scholar
  162. 162.
    Wosik, K., Antel, J., Kuhlmann, T., Bruck, W., Masie, B. and Nalbantoglu, J. (2003):J. Neurochem.,85, 635–644.PubMedCrossRefGoogle Scholar
  163. 163.
    Wu, G. S., Burns, T. F., McDonald, E. R. 3rd, Jiang, W., Meng, R., Krantz, I. D., Kao, G., Gan, D. D., Zhou, J. Y., Muschel, R., Hamilton, S. R., Spinner, N. B., Markowitz, S., Wu, G. and el-Deiry, W. S. (1997):Nat. Genet.,17, 141–143.PubMedCrossRefGoogle Scholar
  164. 164.
    Wu, H. and Lozano, G. (1994):J. Biol. Chem.,269, 20067–20074.PubMedGoogle Scholar
  165. 165.
    Wu, L. and Levine, A. J. (1997):Mol Med.,3, 441–451.PubMedGoogle Scholar
  166. 166.
    Yang, A., Kaghad, M., Wang, Y., Gillet, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D. and McKeon, F. (1998):Mol. Cell.,2, 305–316.PubMedCrossRefGoogle Scholar
  167. 167.
    Yonish-Rouach, E., Borde, J., Gotteland, M., Mishal, Z., Viron, A. and May, E. (1994):Cell Growth Differ.,1, 39–47.Google Scholar
  168. 168.
    Yu, J., Zhang, L., Hwang, P. M., Rago, C., Kinzler, K. W. and Vogelstein, B. (1999):Proc. Natl. Acad. Sci. USA,96, 14517–14522.PubMedCrossRefGoogle Scholar
  169. 169.
    Zhang, L., Yu, J., Park, B. H., Kinzler, K. W. and Vogelstein, B. (2000):Science,290, 989–992.PubMedCrossRefGoogle Scholar
  170. 170.
    Zhao, R., Gish, K., Murphy, M., Yin, Y., Noterman, D., Hoffman, W. H., Tom, E., Mack, D. H. and Levine, A. J. (2000):Genes Dev.,14, 981–993.PubMedCrossRefGoogle Scholar
  171. 171.
    Zhu, X., Yu, Q. S., Cutler, R. G., Culmsee, C. W., Holloway, H. W., Lahiri, D. K., Mattson, M. P. and Greig, N. H. (2002):J. Med. Chem.,45, 5090–5097.PubMedCrossRefGoogle Scholar

Copyright information

© Universidad de Navarra 2004

Authors and Affiliations

  • M. Gomez-Lazaro
    • 1
  • F. J. Fernandez-Gomez
    • 1
  • J. Jordán
    • 1
  1. 1.Centro Regional de Investigaciones Biomédicas, Facultad de MedicinaUniversidad de Castilla-La ManchaAlbaceteSpain

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