Two Polymorphic Variants of Wild-Type p53 Differ Biochemically and Biologically

Abstract

The wild-type p53 protein exhibits a common polymorphism at amino acid 72, resulting in either a proline residue (p53_Pro) or an arginine residue (p53_Arg) at this position. Despite the difference that this change makes in the primary structure of the protein resulting in a difference in migration during sodium dodecyl sulfate-polyacrylamide gel electrophoresis, no differences in the biochemical or biological characteristics of these wild-type p53 variants have been reported. We have recently shown that p53_Arg is significantly more susceptible than p53_Pro to the degradation induced by human papillomavirus (HPV) E6 protein. Moreover, this may result in an increased susceptibility to HPV-induced tumors in homozygous p53_Argindividuals. In further investigating the characteristics of these p53 variants, we now show that both forms are morphologically wild type and do not differ in their ability to bind to DNA in a sequence-specific manner. However, there are a number of differences between the p53 variants in their abilities to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis, and to repress the transformation of primary cells. These observations may have implications for the development of cancers which harbor wild-type p53 sequences and possibly for the ability of such tumors to respond to therapy, depending on their p53 genotype.

ACKNOWLEDGMENTS

We thank Sam Benchimol, Bert Vogelstein, John Jenkins, and Robert Tjian for the pWT3L2, pG13CAT, pCONCAT, and TAF-expressing plasmids, respectively.

G.M. acknowledges support from the National Cancer Institute of Canada, the Cancer Society of Canada, and the Natural Sciences and Engineering Research Council of Canada. L.B. acknowledges support from the Associazione Italian per la Ricerca sul Cancro.