EGR2 induces apoptosis in various cancer cell lines by direct transactivation of BNIP3L and BAK

Unoki, Motoko; Nakamura, Yusuke

doi:10.1038/sj.onc.1206222

Cited by 94 publications

(77 citation statements)

References 30 publications

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“…Two of the IRF-3-dependent genes are known transcription factors that stimulate apoptosis or growth suppression, Zac1 and Egr2/Knox-20. 38,39 In addition, there is an increase in expression of the Fas death domain-associated protein, Daax and a decrease in cyclin A1. Conversely, there is an apparent counterbalance to the promotion of apoptosis with the altered expression of genes that stimulate cellular proliferation.…”

Section: Irf-3 Target Genesmentioning

confidence: 99%

IRF-3-dependent and augmented target genes during viral infection

et al. 2007

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Activation of the transcription factor interferon regulatory factor-3 (IRF-3) is an essential event in the innate immune response to viral infection. To understand the contribution of IRF-3 to host defense, we used a systems biology approach to analyze global gene expression dependent on IRF-3. Comparison of expression profiles in cells from IRF-3 knockout animals or wild-type siblings following viral infection revealed three sets of induced genes, those that are strictly dependent on IRF-3, augmented with IRF-3, or not responsive to IRF-3. Products of identified IRF-3 target genes are involved in innate or acquired immunity, or in the regulation of cell cycle, apoptosis and proliferation. These results reveal the global effects of one transcription factor in the immune response and provide information to evaluate the integrated response to viral infection.

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Section: Irf-3 Target Genesmentioning

confidence: 99%

IRF-3-dependent and augmented target genes during viral infection

et al. 2007

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“…Functional annotation clustering using DAVID software (12) showed that 17 of the up-regulated genes function as activators of apoptosis (Table S2). It has been shown that these genes induce growth arrest and apoptosis in cancer cells (13)(14)(15). Using AnnexinV binding assays and flow cytometry analysis of DU145 cells transfected with GFP-tagged GFP-tagged C/EBPhomologous protein (CHOP), FBJ murine osteosarcoma viral (v-fos) oncogene homolog (FOS) and nuclear receptor subfamily 4, group A, member 2 (NR4A2), we confirmed that overexpression of these proteins induced apoptosis in DU145 cells, whereas GFP alone did not affect cell survival ( Fig.…”

Section: St3-h2a2mentioning

confidence: 99%

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Timofeeva¹,

Tarasova

Zhang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

126

124

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Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.H3K9me3 | peptide inhibitor | prostate cancer | transcription factor S TAT3, a member of the STAT family, is a key signaling protein that transduces extracellular signals to the nucleus and regulates transcription of genes (1). Following ligand stimulation, STAT3 is phosphorylated on Y705 tyrosine residue, dimerizes, and translocates to the nucleus to bind its cognate DNA-response elements, activating gene transcription (1). Constitutively activated STAT3 mediates deregulated growth, survival, and angiogenesis (2, 3). STAT3 is widely recognized as a potential drug target for cancer therapy, and various approaches, including targeting of upstream tyrosine kinases and direct inhibitors of STAT3 dimerization, have been advanced to inhibit STAT3 signaling in cancers (4). However, unphosphorylated STAT3 (U-STAT3) has also been shown to influence gene transcription, both in response to cytokines and in cancer cells, albeit by mechanisms that are distinct from those activated by phosphorylated STAT3 (5). We have developed a highly selective inhibitor of STAT3 ND, ST3-Hel2A-2 (ST3-H2A2), that binds to the N-terminal domain (ND) and inhibits STAT3 signaling (6). STAT3 ND is involved in the interactions of two STAT dimers on neighboring sites to form a more stable tetramer and the interactions with histone-modifier proteins to induce changes in chromatin structure (reviewed in ref. 7). These complex interactions may greatly affect STAT3-dependent transcriptional activity, suggesting that the STAT3 ND mediates important regulatory functions of STAT3 in normal cells (8) and in cancer (9). ST3-H2A2 induces death in breast cancer cells MDA-MB-231 an...

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“…In addition, 5-aza-2 0 -deoxycytidine (a DNA methylation inhibitor) and 4-phenylbutyric acid (a histone deacetylase inhibitor) restore the expression of the epigenetically silenced miR-512-5p in human gastric cancer cells in which miR-512-5p induces apoptosis by suppressing the antiapoptotic Mcl-1 expression (Saito et al, 2009). EGR2 is a tumorsuppressive transcription factor, whose activation induces apoptosis by direct transactivation of BNIP3L and Bak (Unoki and Nakamura, 2003). To this end, the oncogenic miR-150 has been shown to target EGR2 to promote gastric cancer growth (Wu et al, 2010b).…”

Section: Dysregulated Mirnas In Gastric Cancermentioning

confidence: 99%