The codon 72 polymorphic variants of p53 have markedly different apoptotic potential.
The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.
Dumont
Patrick
P
Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111, USA.
Leu
J I-Ju
JI
Della Pietra
Anthony C
AC
George
Donna L
DL
Murphy
Maureen
M
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D018834:Chaperonin 60 / Q000378:metabolism; D003062:Codon / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016158:Genes, p53; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D013489:Suppression, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
D018834:Chaperonin 60; D003062:Codon; D005231:Fatty Acids, Unsaturated; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C018551:glucose-regulated proteins; D001120:Arginine; D011392:Proline; C038753:leptomycin B