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Sall2 is required for proapoptotic Noxa expression and genotoxic stress-induced apoptosis by doxorubicin

The Sall2 transcription factor is deregulated in several cancers; however, little is known about its cellular functions, including its target genes. Recently, we demonstrated that p53 directly regulates Sall2 expression under genotoxic stress. Here, we investigated the role of Sall2 in the context o... Full description

Journal Title: Cell Death and Disease 2015, Vol.6(7), p.e1816
Main Author: D Escobar
Other Authors: M I Hepp , C Farkas , T Campos , N M Sodir , M Morales , C I Álvarez , L Swigart , G I Evan , J L Gutiérrez , R Nishinakamura , A F Castro , R Pincheira
Format: Electronic Article Electronic Article
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ID: ISSN: 2041-4889 ; E-ISSN: 2041-4889 ; DOI: 10.1038/cddis.2015.165
Link: http://dx.doi.org/10.1038/cddis.2015.165
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recordid: nature_a10.1038/cddis.2015.165
title: Sall2 is required for proapoptotic Noxa expression and genotoxic stress-induced apoptosis by doxorubicin
format: Article
creator:
  • D Escobar
  • M I Hepp
  • C Farkas
  • T Campos
  • N M Sodir
  • M Morales
  • C I Álvarez
  • L Swigart
  • G I Evan
  • J L Gutiérrez
  • R Nishinakamura
  • A F Castro
  • R Pincheira
subjects:
  • Apoptosis
  • Genotoxicity
  • Stress
  • Electrophoretic Mobility
  • Doxorubicin
  • Cancer
  • P53 Protein
  • Promoters
  • Leukemia
  • Transcription Factors
  • Embryo Fibroblasts
  • Caspase-3
  • Lymphocytes T
  • Tumor Suppressors
ispartof: Cell Death and Disease, 2015, Vol.6(7), p.e1816
description: The Sall2 transcription factor is deregulated in several cancers; however, little is known about its cellular functions, including its target genes. Recently, we demonstrated that p53 directly regulates Sall2 expression under genotoxic stress. Here, we investigated the role of Sall2 in the context of cellular response to genotoxic stress. In addition, we further examined the Sall2-p53 relationship during genotoxic stress in primary mouse embryo fibroblasts (MEFs), which are derived from Sall2 knockout mice separately, or in combination with the p53ERTAM knock-in mice. We found that the levels of Sall2 mRNA and protein are dynamically modulated in response to doxorubicin. At early times of stress, Sall2 is downregulated, but increases under extension of the stress in a p53-independent manner. Based on caspase-3/7 activities, expression of cleaved poly (ADP-ribose) polymerase, expression of cleaved caspase-3 and induction of proapoptotic proteins, Sall2 expression was correlated with cellular apoptosis. Consequently, Sall2 super(-/-) MEFs have decreased apoptosis, which relates with increased cell viability in response to doxorubicin. Importantly, Sall2 was required for apoptosis even in the presence of fully activated p53. Searching for putative Sall2 targets that could mediate its role in apoptosis, we identified proapoptotic NOXA/PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1). We demonstrated that Sall2 positively regulates Noxa promoter activity. Conserved putative Sall2-binding sites at the NOXA promoter were validated in vitro by electrophoretic mobility shift assay and in vivo by ChIP experiments, identifying NOXA as a novel Sall2 target. In agreement, induction of Noxa protein and mRNA in response to doxorubicin was significantly decreased in Sall2 super(-/-) MEFs. In addition, studies in leukemia Jurkat T cells support the existence of the Sall2/Noxa axis, and the significance of this axis on the apoptotic response to doxorubicin in cancer cells. Our study highlights the relevance of Sall2 in the apoptotic response to extended genotoxic stress, which is important for understanding its role in normal physiology and disease.
language:
source:
identifier: ISSN: 2041-4889 ; E-ISSN: 2041-4889 ; DOI: 10.1038/cddis.2015.165
fulltext: fulltext
issn:
  • 2041-4889
  • 20414889
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titleSall2 is required for proapoptotic Noxa expression and genotoxic stress-induced apoptosis by doxorubicin
creatorD Escobar ; M I Hepp ; C Farkas ; T Campos ; N M Sodir ; M Morales ; C I Álvarez ; L Swigart ; G I Evan ; J L Gutiérrez ; R Nishinakamura ; A F Castro ; R Pincheira
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descriptionThe Sall2 transcription factor is deregulated in several cancers; however, little is known about its cellular functions, including its target genes. Recently, we demonstrated that p53 directly regulates Sall2 expression under genotoxic stress. Here, we investigated the role of Sall2 in the context of cellular response to genotoxic stress. In addition, we further examined the Sall2-p53 relationship during genotoxic stress in primary mouse embryo fibroblasts (MEFs), which are derived from Sall2 knockout mice separately, or in combination with the p53ERTAM knock-in mice. We found that the levels of Sall2 mRNA and protein are dynamically modulated in response to doxorubicin. At early times of stress, Sall2 is downregulated, but increases under extension of the stress in a p53-independent manner. Based on caspase-3/7 activities, expression of cleaved poly (ADP-ribose) polymerase, expression of cleaved caspase-3 and induction of proapoptotic proteins, Sall2 expression was correlated with cellular apoptosis. Consequently, Sall2 super(-/-) MEFs have decreased apoptosis, which relates with increased cell viability in response to doxorubicin. Importantly, Sall2 was required for apoptosis even in the presence of fully activated p53. Searching for putative Sall2 targets that could mediate its role in apoptosis, we identified proapoptotic NOXA/PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1). We demonstrated that Sall2 positively regulates Noxa promoter activity. Conserved putative Sall2-binding sites at the NOXA promoter were validated in vitro by electrophoretic mobility shift assay and in vivo by ChIP experiments, identifying NOXA as a novel Sall2 target. In agreement, induction of Noxa protein and mRNA in response to doxorubicin was significantly decreased in Sall2 super(-/-) MEFs. In addition, studies in leukemia Jurkat T cells support the existence of the Sall2/Noxa axis, and the significance of this axis on the apoptotic response to doxorubicin in cancer cells. Our study highlights the relevance of Sall2 in the apoptotic response to extended genotoxic stress, which is important for understanding its role in normal physiology and disease.
subjectApoptosis ; Genotoxicity ; Stress ; Electrophoretic Mobility ; Doxorubicin ; Cancer ; P53 Protein ; Promoters ; Leukemia ; Transcription Factors ; Embryo Fibroblasts ; Caspase-3 ; Lymphocytes T ; Tumor Suppressors;
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