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Stra13 is induced by genotoxic stress and regulates ionizing-radiation-induced apoptosis.

ABSTRACT: In response to a number of genotoxic stimuli that induce DNA damage in cells, the tumour suppressor p53 is activated resulting in cell cycle arrest or apoptosis. In this study, we have identified stimulated with retinoic acid 13 (Stra13), a basic helix-loop-helix transcription factor, as a regulator of ionizing-radiation-induced apoptosis. We show that Stra13 is induced in response to several DNA-damaging agents in a p53-independent manner. Stra13-/- thymocytes show impaired apoptosis in response to ionizing radiation, and consistently, p53 levels and also expression of its key transcriptional targets Puma and Noxa are reduced in the mutant thymocytes. In vitro, Stra13 regulates p53 levels in a mouse double mutant 2 (Mdm2)-dependent manner by physically interacting with p53 and preventing Mdm2-mediated ubiquitination and nuclear export. Together, our studies provide evidence that Stra13 is involved in DNA-damage-induced apoptosis and indicate its role in tumorigenesis.

SUBMITTER: Thin TH

PROVIDER: S-EPMC1852750 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Stra13 is induced by genotoxic stress and regulates ionizing-radiation-induced apoptosis.

Thin Tin Htwe TH Li Li L Chung Teng-Kai TK Sun Hong H Taneja Reshma R

EMBO reports 20070309 4

In response to a number of genotoxic stimuli that induce DNA damage in cells, the tumour suppressor p53 is activated resulting in cell cycle arrest or apoptosis. In this study, we have identified stimulated with retinoic acid 13 (Stra13), a basic helix-loop-helix transcription factor, as a regulator of ionizing-radiation-induced apoptosis. We show that Stra13 is induced in response to several DNA-damaging agents in a p53-independent manner. Stra13-/- thymocytes show impaired apoptosis in respons ...[more]

PMID: 17347673

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Project 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-/- 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-/- 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.

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Stra13 is induced by genotoxic stress and regulates ionizing-radiation-induced apoptosis.

Publications

Stra13 is induced by genotoxic stress and regulates ionizing-radiation-induced apoptosis.

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