p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes

• Published in: Molecular cancer research Vol. 15; no. 8; pp. 1051 - 1062
• Main Authors: Pappas, Kyrie, Xu, Jia, Zairis, Sakellarios, Resnick-Silverman, Lois, Abate, Francesco, Steinbach, Nicole, Ozturk, Sait, Saal, Lao H, Su, Tao, Cheung, Pamela, Schmidt, Hank, Aaronson, Stuart, Hibshoosh, Hanina, Manfredi, James, Rabadan, Raul, Parsons, Ramon
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01-08-2017
• Subjects: Basic Medicine; Binding sites; Binding Sites - genetics; Cancer; Cancer and Oncology; Cancer och onkologi; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Clinical Medicine; Clonal deletion; Enhancers; Forkhead Box Protein O1 - genetics; FOXO1 protein; Gene deletion; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic transformation; Haploinsufficiency - genetics; Histone Demethylases - genetics; Humans; Klinisk medicin; LKB1 protein; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; MicroRNAs - genetics; Mutation; Neoplasms - genetics; Neoplasms - pathology; Nuclear Proteins - genetics; p53 Protein; Protein Binding; Protein-Serine-Threonine Kinases - genetics; PTEN Phosphohydrolase - genetics; PTEN protein; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Reporter gene; Signal Transduction - genetics; Stress; Stresses; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Tumorigenesis
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-17-0089

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
, and
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
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
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.
In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression.
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