Differential levels of transcription of p53-regulated genes by the arginine/proline polymorphism: p53 with arginine at codon 72 favors apoptosis.
Human populations contain a functional coding polymorphism (codon 72) in the p53 gene. To explore whether this polymorphism alters the transcriptional pattern of p53-regulated genes, the human isogenic cell lines harboring p53 with either the proline or arginine at codon 72 were employed to activate p53-mediated transcription. Thirty-four p53-regulated genes were assayed for their increased levels of mRNA using quantitative real-time PCR. The largest difference between p53-arginine and p53-proline was found with the PERP gene involved in cell-cell adhesion and apoptosis. The most common set of genes that are transcribed better by the p53-arginine protein than the p53-proline protein was found in the apoptotic function (DR-4, NOXA, PUMA, and PIG-3). LIF, a cytokine that is required for optimal reproductive function, was produced at 2x higher levels by the p53-arginine than the p53-proline allele. The genes that induced their mRNAs at the highest levels compared to the baseline tended to be synthesized better by the p53-arginine protein than the p53-proline protein. These molecular studies may help to explain the complicated associations observed between this polymorphism and the incidence of some cancers, the longevity of some populations, and the fecundity of different groups.
Jeong
Byeong-Seon
BS
Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
Hu
Wenwei
W
Belyi
Vladimir
V
Rabadan
Raul
R
Levine
Arnold J
AJ
D017209:Apoptosis / Q000235:genetics*; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003062:Codon / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D003062:Codon; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline