P53 AS A SENSOR OF CARCINOGENIC EXPOSURES - MECHANISMS OF P53 PROTEININDUCTION AND LESSONS FROM P53 GENE-MUTATIONS

The p53 tumor suppressor gene encodes a nuclear phosphoprotein with gr owth inhibiting properties, which is activated in cell exposed to vari ous forms of DNA damaging stress. The development of human cancer ofte n involves inactivation of this suppressor through various mechanisms, including gene deletions and point mutations. Most mutations impair t he specific DNA-binding capacity of p53, therefore allowing cells to p roliferate in conditions where cells with intact p53 function are supp ressed or eliminated. Thus, mutation of p53 may provide a selective ad vantage for the clonal expansion of preneoplastic or neoplastic cells. The diversity of p53 mutations provides a valuable tool to identify i mportant sources of cancer-causing mutation in the human setting. Muta gens and carcinogens damage the genome in characteristic ways, leaving ''mutagen fingerprints'' in DNA. Well-characterised examples of such ''fingerprints'' include G: C to T: A transversions in lung; cancers i n association with cigarette smoke, G: C to T: A transversions at codo n 249 in liver cancers in association with dietary exposure to Aflatox in B1 (AFB1) and CC: GG to TT: AA tandem dipyrimidine transitions in s kin cancers in association with UVB exposure. In addition, mutations a t different codons are not functionally equivalent. The availability o f crystal structures of p53 protein represents an essential developmen t 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 .