Effect of mutation and conformation on the function of p53 in colorectal cancer.
In vitro studies have shown that immunoprecipitation with conformation-specific antibodies allows discrimination between different forms of p53; however, the significance of this has not been determined for human tumours. This study therefore examined p53 conformation in colorectal tumours and correlated this with mutational status and evidence of in vivo p53 downstream activity. Moreover, it was shown that for in vitro cell lines, DNA-damaging agents induce wild-type p53 to form a mutant conformation (PAb240+), with a concomitant rise in p21(WAF-1) expression. Induction of p53-mediated apoptosis, 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 tumours. Mutants with a wild-type conformation gave weak immunohistochemical staining, whereas mutations with flexible conformation (240+/1620+) gave intense positivity. Interestingly, this latter group of flexible mutants was also associated with features of poor prognosis. These studies show that not all 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 treatment for cancer patients.
Department of Pathology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
K M
KM
Webley
A J
AJ
Shorthouse
J A
JA
Royds
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011487:Protein Conformation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins