p53 maintains baseline expression of multiple tumor suppressor genes

Pappas, KyrieIcahn School of Medicine at Mount Sinai,Columbia University (författare)

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.

Xu, JiaIcahn School of Medicine at Mount Sinai (författare)
Zairis, SakellariosColumbia University (författare)
Resnick-Silverman, LoisIcahn School of Medicine at Mount Sinai (författare)
Abate, FrancescoColumbia University (författare)
Steinbach, NicoleColumbia University,Icahn School of Medicine at Mount Sinai (författare)
Ozturk, SaitIcahn School of Medicine at Mount Sinai (författare)
Saal, Lao H.Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Translational Oncogenomics,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups(Swepub:lu)onk-ls0 (författare)
Su, TaoColumbia University (författare)
Cheung, PamelaIcahn School of Medicine at Mount Sinai (författare)
Schmidt, HankIcahn School of Medicine at Mount Sinai (författare)
Aaronson, StuartIcahn School of Medicine at Mount Sinai (författare)
Hibshoosh, HaninaColumbia University (författare)
Manfredi, JamesIcahn School of Medicine at Mount Sinai (författare)
Rabadan, RaulColumbia University (författare)
Parsons, RamonIcahn School of Medicine at Mount Sinai (författare)
Icahn School of Medicine at Mount SinaiColumbia University (creator_code:org_t)

Av författaren/redakt...: Pappas, Kyrie; Xu, Jia; Zairis, Sakellar ...; Resnick-Silverma ...; Abate, Francesco; Steinbach, Nicol ...; visa fler...; Ozturk, Sait; Saal, Lao H.; Su, Tao; Cheung, Pamela; Schmidt, Hank; Aaronson, Stuart; Hibshoosh, Hanin ...; Manfredi, James; Rabadan, Raul; Parsons, Ramon; visa färre...

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