p53 maintains baseline expression of multiple tumor suppressor genes

Kyrie Pappas, Jia Xu, Sakellarios Zairis, Lois Resnick-Silverman, Francesco Abate, Nicole Steinbach, Sait Ozturk, Lao H. Saal, Tao Su, Pamela Cheung, Hank Schmidt, Stuart Aaronson, Hanina Hibshoosh, James Manfredi, Raul Rabadan, Ramon Parsons

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer.

Original languageEnglish
Pages (from-to)1051-1062
Number of pages12
JournalMolecular Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Aug 2017

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