Thus, p53-deficient primary fibroblasts expressing E1A are resistant to apoptosis and become oncogenically transformed ( Lowe et al. Although E1A is a mitogenic oncogene, p53 acts to limit its oncogenic potential. 1997 Samuelson and Lowe 1997), which is reflected by E1A’s remarkable ability to enhance radio- and chemosensitivity ( Lowe et al. For example, the adenovirus E1A oncogene induces p53 and promotes apoptosis in primary cells ( Debbas and White 1993 Lowe and Ruley 1993 Querido et al. Oncogenes can also induce p53, leading to increased apoptosis or premature senescence ( Lowe and Ruley 1993 Hermeking and Eick 1994 Wagner et al. 1997), but whether this provides the primary driving force for p53 mutation in tumors is unclear. In principle, failure of p53 to suppress proliferation following DNA damage might indirectly promote tumor development by allowing the growth and survival of cells with mutations ( Livingstone et al. 1997), a protein that can down-regulate p53 via ubiquitin-mediated proteolysis ( Haupt et al. Phosphorylation at serine-15 prevents p53’s interaction with Mdm2 ( Shieh et al. For example, p53 levels and activity increase following DNA damage owing, in part, to de novo phosphorylation and the accompanying conformational changes ( Shieh et al. 1996 for review, see Ko and Prives 1996 Levine 1997). p53 is a sequence-specific DNA-binding protein that promotes cell-cycle arrest or apoptosis in response to a variety of cellular stresses (for examples, see Kastan et al. 1994 Weinberg 1995).Īlthough the high frequency of p53 mutations in human cancer implies a central role for p53 in tumorigenesis, the signals that trigger p53 in suppressing tumor growth remain poorly defined. Consistent with the relevance of these interactions, p53 and Rb are frequently mutated in human tumors (for review, see Greenblatt et al. For example, many DNA tumor viruses encode proteins that bind and inactivate both p53 and the retinoblastoma (Rb) protein, and inactivation of both is essential for viral transformation ( Lane and Crawford 1979 Linzer and Levine 1979 DeCaprio et al. Similarly, viral oncoproteins target cellular proteins critical for malignant transformation-often the same activities altered by spontaneous mutation in cancer cells. Tumor-specific mutations identify genes essential for normal growth control and reveal fundamental processes involved in tumorigenesis.
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