Effect of mutation and conformation on the function of p53 in colorectal cancer

In vitro studies have shown that immunoprecipitation with conformation-spec ific antibodies allows discrimination between different forms of p53; howev er, the significance of this has not been determined for human tumours, Thi s study therefore examined p53 conformation in colorectal tumours and corre lated this with mutational status and evidence of in vivo p53 downstream ac tivity. Moreover, it was shown that for in vitro cell lines, DNA-damaging a gents induce wildtype p53 to form a mutant conformation (PAb240+), with a c oncomitant rise in p21(WAF-1) expression, Induction of p53-mediated apoptos is, on the other hand, is associated with a wild-type conformation (PAb1620 +). These results were confirmed for wild-type p53 in colorectal tumours, A range of p53 point mutations were found in exons 5-8 in colorectal tumour s. Mutants with a wild-type conformation gave weak immunohistochemical stai ning, whereas mutations with flexible conformation (240+/1620 +) gave inten se positivity, Interestingly, this latter group of flexible mutants was als o associated with features of poor prognosis. These studies show that not a ll p53 mutants are equal; thus, knowledge of the p53 status of a tumour may be required for a more precise prediction of prognosis and response to tre atment for cancer patients, Copyright (C) 2000 John Wiley & Sons, Ltd.