p53 as a sensor of carcinogenic exposures: mechanisms of p53 protein induction and lessons from p53 gene mutations.
The p53 tumor suppressor gene encodes a nuclear phosphoprotein with growth inhibiting properties, which is activated in cell exposed to various forms of DNA damaging stress. The development of human cancer often involves inactivation of this suppressor through various mechanisms, including gene deletions and point mutations. Most mutations impair the specific DNA-binding capacity of p53, therefore allowing cells to proliferate in conditions where cells with intact p53 function are suppressed or eliminated. Thus, mutation of p53 may provide a selective advantage for the clonal expansion of preneoplastic or neoplastic cells. The diversity of p53 mutations provides a valuable tool to identify important sources of cancer-causing mutation in the human setting. Mutagens and carcinogens damage the genome in characteristics ways, leaving "mutagen fingerprints" in DNA. Well-characterised examples of such "fingerprints" include G: C to T: A transversions in lung cancers in association with cigarette smoke, G: C to T: A transversions at codon 249 in liver cancers in association with dietary exposure to Aflatoxin B1 (AFB1) and CC: GG to TT: AA tandem dipyrimidine transitions in skin cancers in association with UVB exposure. In addition, mutations at different codons are not functionally equivalent. The availability of crystal structures of p53 protein represents an essential development in the understanding of the functional properties of p53 mutants. In the future, it is expected that analysis of p53 mutations may provide useful information for the diagnosis, prognosis and therapy of cancer.
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
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Hainaut
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Vähäkangas
D014408:Biomarkers, Tumor; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004249:DNA Damage; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D002274:Carcinogens, Environmental; D016159:Tumor Suppressor Protein p53