p 53 mutations as fingerprints of environmental carcinogens *

Mutations of the p53 tumor suppressor gene occur in a great majority of human cancers. The protein product of p53 gene is involved in DNA damage response. Consequently, p53 gene may be a preferred target for environmental carcinogens, which also act as DNAdamaging agents. This is probably why p53 mutations are frequent in cancers linked to environmental carcinogens. Moreover, these carcinogens leave molecular fingerprints on the p53 gene. Thus, the study of p53 mutation spectra has been a useful approach to implicate suspected carcinogens to different human cancers. This review provides further insight into the significance of p53 mutation spectra in ten common human malignancies (skin, liver, lung, bladder, breast, head and neck, esophagus, stomach and colorectal cancers, and hematological malignancies), in relation with environmental carcinogens. p53 GENE AND ITS CELLULAR FUNCTIONS The human p53 gene is located on the short arm of chromosome 17 (17p13.1) and spans 16–20 kb DNA. The gene has 11 exons coding for an mRNA of 2.2–2.5 kb and a protein of approximately 53 kDa of 393 amino acids. Both exon-intron organization of the gene and amino acid sequence of the protein is conserved between species [1]. p53 is a DNA-binding protein with transcription regulatory activities, and can be divided into three domains, encompassing the amino-terminal domain containing the activation domain, the central core containing its sequence-specific DNA-binding domain, and multifunctional carboxy-terminal domain. p53 protein is present at very low levels in normal cells. Under certain stress, cells are able to upregulate their p53 levels by a post-transcriptional mechanism. The major factors that induce p53 mutations have in common the ability to cause DNA damage. There are two major p53dependent responses. a) Cell cycle arrest: p53 has a clearly defined role in G1/S arrest following DNA damage. p53-mediated cell cycle arrest at the G1/S boundary involves the activation of p21 protein. This protein acts as an inhibitor of cyclin-dependent kinases (CDK), including CDK2 which allows the G1/S transition when complexed with cyclin E. b) Programmed cell death or apoptosis. In some cell types, the induction of p53 by DNA damage leads to a p53-dependent apoptosis rather than cell cycle arrest (reviewed in ref. 2). It was recently reported that p53 is also involved in DNA repair through activation of ribonucleotide reductase gene [3].