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 (p53Pro) or an arginine residue (p53Arg) 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 p53Arg is significantly more susceptible than p53Pro to the degradation induced by human papillomavirus (HPV) E6 protein. Moreover, this may result in an increased susceptibility to HPV-induced tumors in homozygous p53Arg individuals. 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.

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

“…Transient transfection of the various constructs together with a plasmid encoding the green fluorescent protein (eGFP), which served as a control for transfection efficiency, into the p53 null human H1299 cells resulted in the efficient and approximately equal expression of all chimaeric proteins ( Figure 1c). As noted in previous studies (Thomas et al, 1999), 72R polymorphic variant migrated faster than the 72P form, even when in the chimaeric form (Figure 1c), indicating that the chimaerism has not altered this biochemical property of the polymorphs.…”

Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time

“…3,4 Other studies showed that the Pro-variant is less efficient in inducing apoptosis compared with the Argvariant. 25,26 This difference seems to become more pronounced with advancing age. 27 One hypothesis that has been suggested is that individuals homozygous for the Pro-allele preserve their stem cell stock as a result of decreased apoptosis and therefore maintain better cell renewal and homeostasis compared with Arg-carriers.…”

Risk assessment of p53 genotypes and haplotypes in tobacco‐associated leukoplakia and oral cancer patients from eastern india

“…45 More recently, it has been shown that the ability of p53 to interact with the TFIID-associated factors TAFII32 and TAFII70 is much stronger for the Pro-72 form than for the Arg-72 form whereupon the Pro-72 form of p53 has increased transcriptional transactivation capacity. 46 In contrast, analysis of the ability of the 2 polymorphic forms of p53 to induce apoptosis suggests that the 2 polymorphic varieties, though differing in kinetics, are capable of inducing equal levels of apoptosis. 46 In another study, the Arg-72 form of the p53 protein was found to be much more susceptible to HPV E6-mediated degradation compared to the Pro-72 form.…”

“…46 In contrast, analysis of the ability of the 2 polymorphic forms of p53 to induce apoptosis suggests that the 2 polymorphic varieties, though differing in kinetics, are capable of inducing equal levels of apoptosis. 46 In another study, the Arg-72 form of the p53 protein was found to be much more susceptible to HPV E6-mediated degradation compared to the Pro-72 form. 10 In addition, analysis of mutants of p53 within a variety of tumors suggests that mutations in the Arg-72 form of p53 are more common in heterozygous individuals and that this enhances interaction with, and subsequent inactivation of, the p53 family member p73.…”