Manipulating the p53 Gene in the Mouse: Organismal Functions of a Prototype Tumor Suppressor

  • Lawrence A. Donehower
  • Dora Bocangel
  • Melissa Dumble
  • Guillermina Lozano

The early discoveries elucidating p53 function were based on cell culture experiments. Most of our fundamental knowledge of the role of p53 in cell signaling, stress response, cell cycle control, and apoptosis are a result of these in vitro studies (Giaccia and Kastan, 1998; Ko and Prives, 1996; Levine, 1997; Vogelstein et al., 2000). However, a greater depth of understanding was facilitated by the advent first of transgenic mouse methodologies and then by embryonic stem (ES) cell-based genetic manipulations. The sequencing of the mouse genome ( and has greatly simplified and accelerated the generation of null alleles. Methods have been developed to generate single nucleotide substitutions in the germline of mice, and importantly, to generate somatic mutations in genes to study somatic inactivation as occurs in most human cancers. The availability of whole genome analysis at the RNA expression level (arrays) and at the genomic level (array CGH) provides another level of analysis that is sure to provide insights into the molecular changes that lead to the initiation, progression, and maintenance of the tumor phenotype.


Malignant Peripheral Nerve Sheath Tumor Tumor Spectrum 
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. Allemand, I., Anglo, A., Jeantet, A. Y., Cerutti, I., and May, E. (1999). Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis. Oncogene 18, 6521-6530.CrossRefPubMedGoogle Scholar
  2. Appella, E., and Anderson, C. W. (2001). Post-translational modifications and activation of p53 by genotoxic stressess. Eur J Biochem 268, 2764-2772.CrossRefPubMedGoogle Scholar
  3. Armstrong, J. F., Kaufman, M. H., Harrison, D. J., and Clarke, A. R. (1995). High-frequency developmental abnormalities in p53-deficient mice. Curr Biol 5, 931-936.CrossRefPubMedGoogle Scholar
  4. Artandi, S. E., Chang, S., Lee, S. L., Alson, S., Gottlieb, G. J., Chin, L., and DePinho, R. A. (2000). Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641-645.CrossRefPubMedGoogle Scholar
  5. Ashcroft, M., Kubbutat, M. H., and Vousden, K. H. (1999). Regulation of p53 function and stability by phosphorylation. Mol Cell Biol 19, 1751-1758.PubMedGoogle Scholar
  6. Attardi, L. D., and Jacks, T. (1999). The role of p53 in tumour suppression: lessons from mouse models. Cell Mol Life Sci 55, 48-63.CrossRefPubMedGoogle Scholar
  7. Baker, S. J., Preisinger, A. C., Jessup, J. M., Paraskeva, C., Markowitz, S., Willson, J. K., Hamilton, S., and Vogelstein, B. (1990). p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50, 7717-7722.PubMedGoogle Scholar
  8. Bischoff, F. Z., Yim, S. O., Pathak, S., Grant, G., Siciliano, M. J., Giovanella, B. C., Strong, L. C., and Tainsky, M. A. (1990). Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization. Cancer Res 50, 7979-7984.PubMedGoogle Scholar
  9. Cadwell, C., and Zambetti, G. P. (2001). The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth. Gene 277, 15-30.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. Choi, J., and Donehower, L. A. (1999). p53 in embryonic development: maintaining a fine balance. Cell Mol Life Sci 55, 38-47.CrossRefPubMedGoogle Scholar
  12. Cichowski, K., Shih, T. S., Schmitt, E., Santiago, S., Reilly, K., McLaughlin, M. E., Bronson, R. T., and Jacks, T. (1999). Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172-2176.CrossRefPubMedGoogle Scholar
  13. Dittmer, D., Pati, S., Zambetti, G., Chu, S., Teresky, A. K., Moore, M., Finlay, C., and Levine, A. J. (1993). Gain of function mutations in p53. Nat Genet 4, 42-46.CrossRefPubMedGoogle Scholar
  14. Donehower, L. A. (1996). The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol 7, 269-278.CrossRefPubMedGoogle Scholar
  15. Donehower, L. A. (2002). Does p53 affect organismal aging? J Cell Physiol 192, 23-33.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. Donehower, L. A., Harvey, M., Vogel, H., McArthur, M. J., Montgomery, C. A., Jr., Park, S.H., Thompson, T., Ford, R. J., and Bradley, A. (1995). Effects of genetic background on tumorigenesis in p53-deficient mice. Mol Carcinog 14, 16-22.CrossRefPubMedGoogle Scholar
  18. Dragani, T. A. (2003). 10 years of mouse cancer modifier loci: human relevance. Cancer Res 63, 3011-3018.PubMedGoogle Scholar
  19. Duan, W., Ding, H., Subler, M. A., Zhu, W. G., Zhang, H., Stoner, G. D., Windle, J. J., Otterson, G. A., and Villalona-Calero, M. A. (2002). Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice. Oncogene 21, 7831-7838.CrossRefPubMedGoogle Scholar
  20. Eliyahu, D., Raz, A., Gruss, P., Givol, D., and Oren, M. (1984). Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature 312, 646-649.CrossRefPubMedGoogle Scholar
  21. Evans, S. C., Liang, M., Amos, C., Gu, X., and Lozano, G. (2004). A novel genetic modifier of p53, mop1, results in embryonic lethality. In press, Mammalian Genome, 2004.Google Scholar
  22. Finlay, C. A., Hinds, P. W., and Levine, A. J. (1989). The p53 proto-oncogene can act as a suppressor of transformation. Cell 57, 1083-1093.CrossRefPubMedGoogle Scholar
  23. Frebourg, T., Barbier, N., Yan, Y. X., Garber, J. E., Dreyfus, M., Fraumeni, J., Jr., Li, F. P., and Friend, S. H. (1995). Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet 56, 608-615.PubMedGoogle Scholar
  24. Garcia-Cao, I., Garcia-Cao, M., Martin-Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J. C., Blasco, M. A., and Serrano, M. (2002). "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. Embo J 21, 6225-6235.CrossRefPubMedGoogle Scholar
  25. Ghebranious, N., Knoll, B. J., Wu, H., Lozano, G., and Sell, S. (1995). Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. Mol Carcinog 13, 104-111.CrossRefPubMedGoogle Scholar
  26. Ghebranious, N., and Sell, S. (1998). The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice. Hepatology 27, 967-973.CrossRefPubMedGoogle Scholar
  27. Giaccia, A. J., and Kastan, M. B. (1998). The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12, 2973-2983.CrossRefPubMedGoogle Scholar
  28. Godley, L. A., Kopp, J. B., Eckhaus, M., Paglino, J. J., Owens, J., and Varmus, H. E. (1996). Wild-type p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev 10, 836-850.CrossRefPubMedGoogle Scholar
  29. Harvey, M., McArthur, M. J., Montgomery, C. A., Jr., Butel, J. S., Bradley, A., and Donehower, L. A. (1993a). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5, 225-229.CrossRefPubMedGoogle Scholar
  30. 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. (1993b). In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457-2467.PubMedGoogle Scholar
  31. Harvey, M., Vogel, H., Lee, E. Y., Bradley, A., and Donehower, L. A. (1995a). Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res 55, 1146-1151.PubMedGoogle Scholar
  32. Harvey, M., Vogel, H., Morris, D., Bradley, A., Bernstein, A., and Donehower, L. A. (1995b). A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53-deficient mice. Nat Genet 9, 305-311.CrossRefPubMedGoogle Scholar
  33. Hayashi, S., and McMahon, A. P. (2002). Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244, 305-318.CrossRefPubMedGoogle Scholar
  34. Heston, W. E. (1963). Genetics of neoplasia, in Methodology in mammalian genetics. (Burdette W J, ed), Holden-Day, San Francisco, 247-268.Google Scholar
  35. Heston, W. E., and Vlahakis, G. (1971). Mammary tumors, plaques, and hyperplastic alveolar nodules in various combinations of mouse inbred strains and the different lines of the mammary tumor virus. Int J Cancer 7, 141-148.CrossRefPubMedGoogle Scholar
  36. 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
  37. Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C. C. (1991). p53 mutations in human cancers. Science 253, 49-53.CrossRefPubMedGoogle Scholar
  38. Hundley, J. E., Koester, S. K., Troyer, D. A., Hilsenbeck, S. G., Subler, M. A., and Windle, J.J. (1997). Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol Cell Biol 17, 723-731.PubMedGoogle Scholar
  39. Hupp, T. R., Meek, D. W., Midgley, C. A., and Lane, D. P. (1992). Regulation of the specific DNA binding function of p53. Cell 71, 875-886.CrossRefPubMedGoogle Scholar
  40. Hussain, S. P., and Harris, C. C. (1998). Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58, 4023-4037.PubMedGoogle Scholar
  41. Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., and Weinberg, R. A. (1994). Tumor spectrum analysis in p53-mutant mice. Curr Biol 4, 1-7.CrossRefPubMedGoogle Scholar
  42. Jeffrey, P. D., Gorina, S., and Pavletich, N. P. (1995). Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science 267, 1498-1502.CrossRefPubMedGoogle Scholar
  43. Jones, J. M., Attardi, L., Godley, L. A., Laucirica, R., Medina, D., Jacks, T., Varmus, H. E., and Donehower, L. A. (1997). Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis. Cell Growth Differ 8, 829-838.PubMedGoogle Scholar
  44. Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., and Berns, A. (2001). Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29, 418-425.CrossRefPubMedGoogle Scholar
  45. Kapoor, M., and Lozano, G. (1998). Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc Natl Acad Sci U S A 95, 2834-2837.CrossRefPubMedGoogle Scholar
  46. Klatt, P., and Serrano, M. (2003). Engineering cancer resistance in mice. Carcinogenesis 24, 817-826.CrossRefPubMedGoogle Scholar
  47. Klein, M. A., Ruedi, D., Nozaki, M., Dell, E. W., Diserens, A. C., Seelentag, W., Janzer, R.C., Aguzzi, A., and Hegi, M. E. (2000). Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant. Oncogene 19, 5329-5337.CrossRefPubMedGoogle Scholar
  48. Knudson, A. G., Jr. (1986). Genetics of human cancer. Annu Rev Genet 20, 231-251.CrossRefPubMedGoogle Scholar
  49. Ko, L. J., and Prives, C. (1996). p53: puzzle and paradigm. Genes Dev 10, 1054-1072.CrossRefPubMedGoogle Scholar
  50. Kuperwasser, C., Hurlbut, G. D., Kittrell, F. S., Dickinson, E. S., Laucirica, R., Medina, D., Naber, S. P., and Jerry, D. J. (2000). Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol 157, 2151-2159.PubMedGoogle Scholar
  51. Lavigueur, A., Maltby, V., Mock, D., Rossant, J., Pawson, T., and Bernstein, A. (1989). High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9, 3982-3991.PubMedGoogle Scholar
  52. Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88, 323-331.CrossRefPubMedGoogle Scholar
  53. Li, B., Rosen, J. M., McMenamin-Balano, J., Muller, W. J., and Perkins, A. S. (1997). neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. Mol Cell Biol 17, 3155-3163.PubMedGoogle Scholar
  54. Liu, G., McDonnell, T. J., Montes de Oca Luna, R., Kapoor, M., Mims, B., El-Naggar, A. K., and Lozano, G. (2000). High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci U S A 97, 4174-4179.CrossRefPubMedGoogle Scholar
  55. Liu, G., Parant, J. M., Lang, G., Chau, P., Chavez-Reyes, A., El-Naggar, A. K., Multani, A., Chang, S., and Lozano, G. (2004). Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36, 63-68.CrossRefPubMedGoogle Scholar
  56. Lozano, G., and Liu, G. (1998). Mouse models dissect the role of p53 in cancer and development. Semin Cancer Biol 8, 337-344.CrossRefPubMedGoogle Scholar
  57. Lu, H., Taya, Y., Ikeda, M., and Levine, A. J. (1998). Ultraviolet radiation, but not gamma radiation or etoposide-induced DNA damage, results in the phosphorylation of the murine p53 protein at serine-389. Proc Natl Acad Sci U S A 95, 6399-6402.CrossRefPubMedGoogle Scholar
  58. Ludwig, R. L., Bates, S., and Vousden, K. H. (1996). Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 16, 4952-4960.PubMedGoogle Scholar
  59. Luo, J. L., Tong, W. M., Yoon, J. H., Hergenhahn, M., Koomagi, R., Yang, Q., Galendo, D., Pfeifer, G. P., Wang, Z. Q., and Hollstein, M. (2001a). UV-induced DNA damage and mutations in Hupki (human p53 knock-in) mice recapitulate p53 hotspot alterations in sunexposed human skin. Cancer Res 61, 8158-8163.PubMedGoogle Scholar
  60. Luo, J. L., Yang, Q., Tong, W. M., Hergenhahn, M., Wang, Z. Q., and Hollstein, M. (2001b). Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool. Oncogene 20, 320-328.CrossRefPubMedGoogle Scholar
  61. Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A., Thorner, M., and Scrable, H. (2004). Modulation of mammalian life span by the short isoform of p53. Genes Dev 18, 306-319.CrossRefPubMedGoogle Scholar
  62. 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., and Tainsky, M. A. (1990). Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. [see comments.]. Science 250, 1233-1238.CrossRefPubMedGoogle Scholar
  63. Mao, J. H., and Balmain, A. (2003). Genomic approaches to identification of tumour-susceptibility genes using mouse models. Curr Opin Genet Dev 13, 14-19.CrossRefPubMedGoogle Scholar
  64. 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.CrossRefPubMedGoogle Scholar
  65. Muller, A. J., Teresky, A. K., and Levine, A. J. (2000). A male germ cell tumor susceptibility-determining locus, pgct1, identified on murine chromosome 13. Proc Natl Acad Sci U S A 97, 8421-8426.CrossRefPubMedGoogle Scholar
  66. Murphy, E. D. (1966). Characteristic tumors, in Biology of the laboratory mouse, 2nd ed. (Green, E L, ed), McGraw-Hill, New York, 521-562.Google Scholar
  67. Nakamura, T., Pichel, J. G., Williams-Simons, L., and Westphal, H. (1995). An apoptotic defect in lens differentiation caused by human p53 is rescued by a mutant allele. Proc Natl Acad Sci U S A 92, 6142-6146.CrossRefPubMedGoogle Scholar
  68. Overholtzer, M., Rao, P. H., Favis, R., Lu, X. Y., Elowitz, M. B., Barany, F., Ladanyi, M., Gorlick, R., and Levine, A. J. (2003). The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc Natl Acad Sci U S A 100, 11547-11552.CrossRefPubMedGoogle Scholar
  69. Paige, A. J.(2003). Redefining tumour suppressor genes: exceptions to the two-hit hypothesis. Cell Mol Life Sci 60, 2147-2163.CrossRefPubMedGoogle Scholar
  70. Parant, J. M., and Lozano, G. (2003). Disrupting TP53 in mouse models of human cancers. Hum Mutat 21, 321-326.CrossRefPubMedGoogle Scholar
  71. Possemato, R., Eggan, K., Moeller, B. J., Jaenisch, R., and Jackson-Grusby, L. (2002). Flp recombinase regulated lacZ expression at the ROSA26 locus. Genesis 32, 184-186.CrossRefPubMedGoogle Scholar
  72. Purdie, C. A., Harrison, D. J., Peter, A., Dobbie, L., White, S., Howie, S. E., Salter, D. M., Bird, C. C., Wyllie, A. H., and Hooper, M. L. (1994). Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9, 603-609.PubMedGoogle Scholar
  73. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E., and Jacks, T. (2000). Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain- specific effects. Nat Genet 26, 109-113.CrossRefPubMedGoogle Scholar
  74. Rowan, S., Ludwig, R. L., Haupt, Y., Bates, S., Lu, X., Oren, M., and Vousden, K. H. (1996). Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. Embo J 15, 827-838.PubMedGoogle Scholar
  75. Sah, V. P., Attardi, L. D., Mulligan, G. J., Williams, B. O., Bronson, R. T., and Jacks, T. (1995). A subset of p53-deficient embryos exhibit exencephaly. Nat Genet 10, 175-180.CrossRefPubMedGoogle Scholar
  76. Schmitt, C. A., Fridman, J. S., Yang, M., Baranov, E., Hoffman, R. M., and Lowe, S. W. (2002). Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1, 289-298.CrossRefPubMedGoogle Scholar
  77. Shen, H. M., and Ong, C. N. (1996). Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis. Mutat Res 366, 23-44.PubMedGoogle Scholar
  78. Shieh, S. Y., Ikeda, M., Taya, Y., and Prives, C. (1997). DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325-334.CrossRefPubMedGoogle Scholar
  79. Shieh, S. Y., Taya, Y., and Prives, C. (1999). DNA damage-inducible phosphorylation of p53 at N-terminal sites including a novel site, Ser20, requires tetramerization. Embo J 18, 1815-1823.CrossRefPubMedGoogle Scholar
  80. Sigal, A., and Rotter, V. (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60, 6788-6793.PubMedGoogle Scholar
  81. Slingerland, J. M., Jenkins, J. R., and Benchimol, S. (1993). The transforming and suppressor functions of p53 alleles: effects of mutations that disrupt phosphorylation, oligomerization and nuclear translocation. Embo J 12, 1029-1037.PubMedGoogle Scholar
  82. Sluss, H. K., Armata, H., Gallant, J., and Jones, S. N. (2004). Phosphorylation of serine 18 regulates distinct p53 functions in mice. Mol Cell Biol 24, 976-984.CrossRefPubMedGoogle Scholar
  83. Soussi, T., and Beroud, C. (2003). Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum Mutat 21, 192-200.CrossRefPubMedGoogle Scholar
  84. 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 348, 747-749.CrossRefPubMedGoogle Scholar
  85. Storer, R. D., French, J. E., Haseman, J., Hajian, G., LeGrand, E. K., Long, G. G., Mixson, L. A., Ochoa, R., Sagartz, J. E., and Soper, K. A. (2001). P53+/- hemizygous knockout mouse: overview of available data. Toxicol Pathol 29 Suppl, 30-50.Google Scholar
  86. Sturzbecher, H. W., Brain, R., Addison, C., Rudge, K., Remm, M., Grimaldi, M., Keenan, E., and Jenkins, J. R. (1992). A C-terminal alpha-helix plus basic region motif is the major structural determinant of p53 tetramerization. Oncogene 7, 1513-1523.PubMedGoogle Scholar
  87. Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T., and Van Dyke, T. (1994). p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78, 703-711.CrossRefPubMedGoogle Scholar
  88. Tsukada, T., Tomooka, Y., Takai, S., Ueda, Y., Nishikawa, S., Yagi, T., Tokunaga, T., Takeda, N., Suda, Y., Abe, S., and et al. (1993). Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene 8, 3313-3322.PubMedGoogle Scholar
  89. Tyner, S. D., Choi, J., Laucirica, R., Ford, R. J., and Donehower, L. A. (1999). Increased tumor cell proliferation in murine tumors with decreasing dosage of wild-type p53. Mol Carcinog 24, 197-208.CrossRefPubMedGoogle Scholar
  90. Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45-53.CrossRefPubMedGoogle Scholar
  91. Unger, T., Juven-Gershon, T., Moallem, E., Berger, M., Vogt Sionov, R., Lozano, G., Oren, M., and Haupt, Y. (1999). Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. Embo J 18, 1805-1814.CrossRefPubMedGoogle Scholar
  92. Varley, J. M., Thorncroft, M., McGown, G., Appleby, J., Kelsey, A. M., Tricker, K. J., Evans, D. G., and Birch, J. M. (1997). A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. Oncogene 14, 865-871.CrossRefPubMedGoogle Scholar
  93. Venkatachalam, S., Shi, Y. P., Jones, S. N., Vogel, H., Bradley, A., Pinkel, D., and Donehower, L. A. (1998). Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. Embo J 17, 4657-4667.CrossRefPubMedGoogle Scholar
  94. Venkatachalam, S., Tyner, S. D., Pickering, C. R., Boley, S., Recio, L., French, J. E., and Donehower, L. A. (2001). Is p53 haploinsufficient for tumor suppression? Implications for the p53+/- mouse model in carcinogenicity testing. Toxicol Pathol 29, 147-154.CrossRefPubMedGoogle Scholar
  95. Vogelstein, B., Lane, D., and Levine, A. J. (2000). Surfing the p53 network. Nature 408, 307-310.CrossRefPubMedGoogle Scholar
  96. Waterman, M. J., Stavridi, E. S., Waterman, J. L., and Halazonetis, T. D. (1998). ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nat Genet 19, 175-178.CrossRefPubMedGoogle Scholar
  97. Williams, B. O., Remington, L., Albert, D. M., Mukai, S., Bronson, R. T., and Jacks, T. (1994). Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7, 480-484.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Lawrence A. Donehower
    • 1
  • Dora Bocangel
    • 1
  • Melissa Dumble
    • 1
  • Guillermina Lozano
    • 2
  1. 1.Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonUSA
  2. 2.Department of Molecular Genetics, Section of Cancer GeneticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations