278410 The p53Pro72Arg Polymorphism Specifies a Balance Between Stem Cell Renewal and Cancer Progression

Wednesday, October 31, 2012: 9:42 AM
Somerset East (Westin )
Marc R. Birtwistle1,2, Emily Cloessner2, Josephine Tidwell2, Megan Clendenning2 and Philip Buckhaults2, (1)Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, (2)Cancer Research Center, Georgia Health Sciences University, Augusta, GA

We studied the common Pro72Arg polymorphism of the p53 transcription factor, which is mutated or lost in over half of human cancers, and found that the Pro/Pro genotype, which is enriched in African American populations, is significantly associated with a 6 year decrease in the mean age of colon cancer diagnosis, independent of race. To explore the hypothesis that Pro- and Arg-specific gene expression patterns may contribute this decrease, we used somatic cell knockout techniques to construct p53 hemizygous or knockout variants of the RKO colon carcinoma cell line, subjected these cells to the DNA damaging agent etoposide, and then performed next generation RNA sequencing experiments. Our analysis of the results revealed not only a comprehensive list of 632 p53-dependent transcripts, but also 83 Arg-specific and 65 Pro-specific transcripts. Bioinformatic analysis showed that Pro-specific gene expression patterns are significantly associated with poorly differentiated cancer and stem cell function, whereas those of Arg are associated with differentiation and downregulation of DNA repair. The transcriptional co-repressor PRDM1b, which recruits H3K9 and H3K27 trimethyl repressive chromatin marks and is necessary for proper differentiation of stem cells, was identified and validated as an Arg-specific target. Taken together, our results suggest that the p53 codon72 polymorphism defines a balance between increased protection from cancer at the expense of stem cell number and longevity.

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