p53, apoptosis and human cancers.
More than half of human cancers contain p53 mutations. Structural analyses of p53-DNA interactions indicate that hot spots of p53 mutation are often either involved in direct contact with target DNA or those that maintain specific conformation of p53. One significant consequence of the loss of wild type p53 function is inhibition of apoptosis, which may be through the inability of mutant p53 to transcriptionally activate bax gene expression. Quantitative correlation among ultraviolet-induced p53 mutations of keratocytes, inhibition of apoptosis and the development of squamous cell cancer of the skin further suggest a central role of inhibited apoptosis between p53 mutations and tumorigenesis. Hypoxia-mediated selection for p53 mutant cells with diminished apoptotic potential in solid tumors may account for the high prevalence of p53 mutations in human cancers. Our increasing understanding of the role of p53 mutations and apoptosis in human cancers has also provided some insights into strategies for anticancer therapy. Studies reconstituting the wild-type p53 through gene therapy have been encouraging. More importantly, further elucidation of the mechanisms of therapy-induced p53-independent apoptosis in cancer cells will facilitate the development of more efficient, less toxic anticancer therapy.
Wang
T H
TH
Department of Obstetrics and Gynecology, University of Tennessee Medical Center at Knoxville, USA.
Wang
H S
HS
D017209:Apoptosis; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000628:therapy