Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.

Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.

SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neu...

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Autores principales: Carlos Farkas, Carla P Martins, David Escobar, Matias I Hepp, Ariel F Castro, Gerard Evan, José L Gutiérrez, Robert Warren, David B Donner, Roxana Pincheira
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2013
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Acceso en línea:https://doaj.org/article/02d66ecedf9e45539f3f30d3d29169cb
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spelling oai:doaj.org-article:02d66ecedf9e45539f3f30d3d29169cb2021-11-18T08:56:30ZWild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.1932-620310.1371/journal.pone.0073817https://doaj.org/article/02d66ecedf9e45539f3f30d3d29169cb2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24040083/?tool=EBIhttps://doaj.org/toc/1932-6203SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the p53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative p53 half sites along the promoter region. Either overexpression of wild-type p53 or induction of the endogenous p53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However R175H, R249S, and R248W p53 mutants, frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity, suggesting that p53 specific binding to DNA is important for the regulation of SALL2. Electrophoretic mobility shift assay demonstrated binding of p53 to one of the identified p53 half sites in the Sall2 promoter, and chromatin immunoprecipitation analysis confirmed in vivo interaction of p53 with the promoter region of Sall2 containing this half site. Importantly, by using a p53ER (TAM) knockin model expressing a variant of p53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that p53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosensitive tissues in vivo. Thus, our finding indicates that p53 represses SALL2 expression in a context-specific manner, adding knowledge to the understanding of SALL2 gene regulation, and to a potential mechanism for its deregulation in cancer.Carlos FarkasCarla P MartinsDavid EscobarMatias I HeppAriel F CastroGerard EvanJosé L GutiérrezRobert WarrenDavid B DonnerRoxana PincheiraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e73817 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Carlos Farkas
Carla P Martins
David Escobar
Matias I Hepp
Ariel F Castro
Gerard Evan
José L Gutiérrez
Robert Warren
David B Donner
Roxana Pincheira
Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
description SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the p53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative p53 half sites along the promoter region. Either overexpression of wild-type p53 or induction of the endogenous p53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However R175H, R249S, and R248W p53 mutants, frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity, suggesting that p53 specific binding to DNA is important for the regulation of SALL2. Electrophoretic mobility shift assay demonstrated binding of p53 to one of the identified p53 half sites in the Sall2 promoter, and chromatin immunoprecipitation analysis confirmed in vivo interaction of p53 with the promoter region of Sall2 containing this half site. Importantly, by using a p53ER (TAM) knockin model expressing a variant of p53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that p53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosensitive tissues in vivo. Thus, our finding indicates that p53 represses SALL2 expression in a context-specific manner, adding knowledge to the understanding of SALL2 gene regulation, and to a potential mechanism for its deregulation in cancer.
format article
author Carlos Farkas
Carla P Martins
David Escobar
Matias I Hepp
Ariel F Castro
Gerard Evan
José L Gutiérrez
Robert Warren
David B Donner
Roxana Pincheira
author_facet Carlos Farkas
Carla P Martins
David Escobar
Matias I Hepp
Ariel F Castro
Gerard Evan
José L Gutiérrez
Robert Warren
David B Donner
Roxana Pincheira
author_sort Carlos Farkas
title Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
title_short Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
title_full Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
title_fullStr Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
title_full_unstemmed Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
title_sort wild type p53 transcriptionally represses the sall2 transcription factor under genotoxic stress.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/02d66ecedf9e45539f3f30d3d29169cb
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