Mutant p53 Reactivation as a Novel Strategy for Cancer Therapy
Inactivation of the p53 tumor suppressor by point mutation occurs in a large fraction of human tumors, including almost all tumor types (see p53 Mutation database at http://www.iarc.fr/p53). A majority of p53 mutations are missense mutations that give rise to the expression of mutant p53 proteins with one amino acid substitution. This pattern of mutation stands in sharp contrast to those of most other tumor suppressor genes, e.g. the Rb and p16 genes, which are frequently inactivated by homozygous deletion, smaller deletions or promoter methylation that either results in complete lack of expression of the protein, or expression of a truncated unstable protein. This suggests that p53 mutation not only serves to inactivate p53 but that expression of mutant p53 itself may provide a selective advantage to tumor cells and promote tumor growth. First, point mutant p53 proteins may act in a dominant negative manner, i.e. inhibit the activity of a wild type allele present in the same cell through hetero-oligomerization that forces wild type p53 to adopt a mutant conformation (Milner and Medcalf 1991). In addition, mutant p53 proteins may have acquired novel activites that could support the growth of tumors. These so called gain-of-function (GOF) activities of mutant p53 could involve promiscuous DNA binding and illegitimate activation of target genes, such as the c-Myc oncogene, the multidrug resistance gene (MDR1), VEGF, and the dUTPase gene ((Frazier et al. 1998; Pugacheva et al. 2002; Tsang et al. 2003); www.iarc.fr/p53), whose activation could contribute to tumor development. Moreover, mutant p53 could enhance cell cycle progression and/or cell survival through novel interactions with cellular protein partners, as examplified by the binding of mutant p53 to p73 and other p53 family members (Di Como et al. 1999; Marin and Kaelin 2000; Strano et al. 2002; Monti et al. 2003; Strano and Blandino 2003).
KeywordsCore Domain National Cancer Institute Database Transcription Activation Function Mutant Conformation dUTPase Gene
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