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p53 maintains baseline expression of multiple tumor suppressor genes

Pappas, Kyrie; Xu, Jia; Zairis, Sakellarios; Resnick-Silverman, Lois; Abate, Francesco; Steinbach, Nicole; Ozturk, Sait; Saal, Lao H. LU ; Su, Tao and Cheung, Pamela, et al. (2017) In Molecular Cancer Research 15(8). p.1051-1062
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... (More)

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.

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Molecular Cancer Research
volume
15
issue
8
pages
12 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85026624819
  • wos:000406681200009
ISSN
1541-7786
DOI
10.1158/1541-7786.MCR-17-0089
language
English
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yes
id
39ae8add-130b-4e5a-9014-c8484d88f2c9
date added to LUP
2017-08-23 14:35:15
date last changed
2018-04-29 04:41:42
@article{39ae8add-130b-4e5a-9014-c8484d88f2c9,
  abstract     = {<p>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.</p>},
  author       = {Pappas, Kyrie and Xu, Jia and Zairis, Sakellarios and Resnick-Silverman, Lois and Abate, Francesco and Steinbach, Nicole and Ozturk, Sait and Saal, Lao H. and Su, Tao and Cheung, Pamela and Schmidt, Hank and Aaronson, Stuart and Hibshoosh, Hanina and Manfredi, James and Rabadan, Raul and Parsons, Ramon},
  issn         = {1541-7786},
  language     = {eng},
  month        = {08},
  number       = {8},
  pages        = {1051--1062},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Research},
  title        = {p53 maintains baseline expression of multiple tumor suppressor genes},
  url          = {http://dx.doi.org/10.1158/1541-7786.MCR-17-0089},
  volume       = {15},
  year         = {2017},
}