Abstract
p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress.
Highlights
IntroductionFrequent mutations of the p53 gene located at residues R175, G245, R248, R249, R273, and R282 found in human cancers do not regulate the p53 target gene expression due to DNA contact or structural alteration as transcription factors [6,7]
Division of KM Data, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Division of KM Science Research, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Abstract: p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells
We reported an isogenic line for p53 codon 72, including proline 72 (P72) and R72, established by a BAC-mediated HR system based on the human induce pluripotent stem cells (iPSCs) identified as retaining p53 heterozygosity for p53 codon 72 [17]
Summary
Frequent mutations of the p53 gene located at residues R175, G245, R248, R249, R273, and R282 found in human cancers do not regulate the p53 target gene expression due to DNA contact or structural alteration as transcription factors [6,7] This functional alteration of p53 due to these mutations leads to serious problems in maintaining genome stability and cell integrity, resulting in cellular transformation [8,9]. In addition to these mutations, as a frequent polymorphism that may have an impact on p53 function, the p53 protein has an amino acid substitution at codon 72, encoding either arginine 72 (R72) variant or proline 72 (P72) variant. R72 enhances pro-apoptotic gene expression more effectively than P72, leading to effective apoptosis [11,12,13], whereas
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