Smad7 Protein Induces Interferon Regulatory Factor 1-dependent Transcriptional Activation of Caspase 8 to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis

Kim, Hye-Youn; Kim, Joo-Young; Ha, Huyen Trang; Kim, Youngmi; Bae, Eun Ju; Kim, Tae Hyung; Lee, Kang Choon; Kim, Seong‐Jin

doi:10.1074/jbc.m112.400408

Cited by 24 publications

(20 citation statements)

References 62 publications

(33 reference statements)

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“…(d) The expression of the EGFP reporter containing the 3′-UTR of IRF1 was inhibited when miR-23a was over-expressed. (e) The over-expression of IRF1 suppressed cellular proliferation and promoted apoptosis [29], [30]. (f) The expression of IRF1 was sufficient to counteract the miR-23a-mediated promotion of cellular proliferation and the repression of cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

Zhang

et al. 2013

PLoS ONE

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MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR-23a bound to the IRF1 mRNA 3′UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently up-regulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level.

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Section: Discussionmentioning

confidence: 99%

miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

Zhang

et al. 2013

PLoS ONE

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“…Accumulating evidence has demonstrated that I-SMADs may act as transcriptional co-activators that are independent of the R-SMAD signaling 41, 42 . The C-terminus of the I-SMADs has a MH2 domain that is indeed conserved among all SMAD proteins.…”

Section: Discussionmentioning

confidence: 99%

Infection of Hepatocytes With HCV Increases Cell Surface Levels of Heparan Sulfate Proteoglycans, Uptake of Cholesterol and Lipoprotein, and Virus Entry by Up-regulating SMAD6 and SMAD7

et al. 2017

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BACKGROUND & AIMS The signaling molecule and transcriptional regulator SMAD6, which inhibits the transforming growth factor beta (TGFB) signaling pathway, is required for infection of hepatocytes by hepatitis C virus (HCV). We investigated the mechanisms by which SMAD6, and another inhibitory SMAD (SMAD7), promote HCV infection in human hepatoma cells and hepatocytes. METHODS We infected Huh7 and Huh7.5.1 cells and primary human hepatocytes with JFH1 HCVcc; we measured HCV binding, intracellular levels of HCV RNA, and expression of target genes. HCV entry in HepG2/miR122/CD81 cells, which support entry and replication of HCV, were transfected with small-interfering (si)RNAs and gene expression profiles were analyzed. Uptake of labeled low-density lipoprotein (LDL) and cholesterol were measured. Cell surface proteins were quantified by flow cytometry. We obtained liver biopsy samples from 69 patients with chronic HCV infection and 19 uninfected individuals (controls) and measured levels of syndecan 1 (SDC1), SMAD7, and SMAD6 mRNAs. RESULTS siRNA knockdown of SMAD6 blocked the binding and infection of cell lines and primary human hepatocytes by HCV, whereas SMAD6 overexpression increased infection by HCV. We found levels of mRNAs encoding heparan sulfate proteoglycans (HSPGs), particularly SDC1 mRNA, and cell surface levels of heparan sulfate to be reduced in cells following SMAD6 knockdown. SMAD6 knockdown also reduced transcription of gene encoding lipoprotein and cholesterol uptake receptors, including the LDL receptor (LDLR), the very LDLR (VLDLR), and the scavenger receptor class B member 1 (SCARB1 or SR-BI) in hepatocytes; SMAD6 knockdown also reduced cell uptake of cholesterol and lipoprotein. Overexpression of SMAD6 increased expression of these genes. Similar effects were observed with knockdown and overexpression of SMAD7. HCV infection of cells increased expression of SMAD6, which required the activity of nuclear factor-kB (NF-kB), but not TGFB. Liver tissues from patients with chronic HCV infection had significantly higher levels of SMAD6, SMAD7, and HSPG mRNAs than controls. Conclusions In studies of hepatoma cell lines and human primary hepatocytes, we found that infection with HCV leads to activation of NF-κB, leading to increased expression of SMAD6 and SMAD7. Upregulation of SMAD6 and SMAD7 lead to increased expression of HSPGs, such as SDC1, as well as LDLR, VLDLR, and SR-BI, which promote HCV entry and propagation, as well as cell uptake of cholesterol and lipoprotein.

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“…Using Ucn, CRH family peptide, our recent research demonstrated that Ucn blocked normal TGFβ1‐Smad2/3 signaling through Smad7 up‐regulation, implying Ucn might inhibit Smad7 degradation to block Smad2/3 phosphorylation. It is reported that Smad7 in apoptosis‐resistant MCF‐7 cells markedly sensitized the cells to TRAIL‐induced cell death [Hong et al, ]. In other in vitro models, Smad7 are demonstrated to potentiate cell apoptosis [Lallemand et al, ; Hong et al, ; Wang et al, ].…”

Section: Discussionmentioning

confidence: 99%

Urocortin Attenuates TGFβ1‐Induced Snail1 and Slug Expressions: Inhibitory Role of Smad7 in Smad2/3 Signaling in Breast Cancer Cells

Jin

Zhu

Wang

et al. 2015

J of Cellular Biochemistry

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Corticortropin-releasing hormone (CRH) family are multifunctional endocrine-factors that regulate proliferation, apoptosis, and migration of various types of cancer cells. Deregulation of the transforming growth factor β1(TGFβ1) signal transduction promotes aggressive metastatic properties in late-stage breast cancers. We previously have demonstrated in breast cancer cell line that CRH suppressed TGFβ1-induced Epithelial-Mesenchymal Transition (EMT) via induction of E-cadherin. Our present data in MCF-7 and MDA-MB-231 cells showed that Urocortin (Ucn, a member of CRH family) inhibited TGFβ1 signaling by reducing Smad2/3 activation and subsequent nuclear translocation through increasing Smad7 expression, leading to downregulation of Snail1 and Slug, the two EMT promoters. We further found that Antalarmin (CRH receptor type 1, CRHR1 antagonist) and Antisauvagine-30 (CRH receptor type2, CRHR2 antagonist) abrogated the effects of Ucn on TGFβ1 signaling, implying that both active CRHR1 and CRHR2 participate in Ucn-repressed TGFβ1 signaling. Our findings, for the fist time, identify Ucn as a potential mediator that inhibits oncogenic signaling by TGFβ1 and suggest that activating CRHR1 and R2 may prove effective in diminishing breast cancer progression stimulated by TGFβ1.

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Smad7 Protein Induces Interferon Regulatory Factor 1-dependent Transcriptional Activation of Caspase 8 to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis

Cited by 24 publications

References 62 publications

miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

Infection of Hepatocytes With HCV Increases Cell Surface Levels of Heparan Sulfate Proteoglycans, Uptake of Cholesterol and Lipoprotein, and Virus Entry by Up-regulating SMAD6 and SMAD7

Urocortin Attenuates TGFβ1‐Induced Snail1 and Slug Expressions: Inhibitory Role of Smad7 in Smad2/3 Signaling in Breast Cancer Cells

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