Glycogen synthase kinase-3β regulates etoposide-induced apoptosis via Bcl-2 mediated caspase-3 activation in C3H10T1/2 cells

Yun, Sun-Il; Yoon, Hyung-Young; Chung, Yoon‐Sok

doi:10.1007/s10495-009-0348-4

Cited by 21 publications

(13 citation statements)

References 20 publications

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“…Consistent with previous results in INS-1E ␤-cells (14), we found that cytokine treatment increased cleaved caspase3 activity in the MIN6 ␤-cells, whereas treatment with EX4 decreased cytokine-induced caspase3 levels. However, in addition to proliferation, several downstream mediators of cWnt signaling has been found to regulate apoptosis in a variety of cell types, including ␤-cells (35)(36)(37)(38)(39)(40)(41)(42). The present study shows, for the first time, that Rspo1 inhibits cytokine-induced apoptosis in the MIN6 ␤-cells.…”

Section: Discussionsupporting

confidence: 50%

R-spondin-1 Is a Novel β-Cell Growth Factor and Insulin Secretagogue

Wong

Yeung

Schultz

et al. 2010

Journal of Biological Chemistry

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R-spondin-1 (Rspo1) is an intestinal growth factor known to exert its effects through activation of the canonical Wnt (cWnt) signaling pathway and subsequent expression of cWnt target genes. We have detected Rspo1 mRNA in murine islets and the murine MIN6 and ␤TC ␤-cell lines, and Rspo1 protein in MIN6 ␤-cells. Rspo1 activated cWnt signaling in MIN6 ␤-cells by increasing nuclear ␤-catenin and c-myc, a cWnt target gene. Rspo1 also induced insulin mRNA expression in MIN6 cells. Analysis of MIN6 and mouse ␤-cell proliferation by [ 3 H]thymidine and BrdU incorporation, respectively, revealed that Rspo1 stimulated cell growth. Incubation of MIN6 and mouse ␤-cells with cytokines (IL1␤/TNF␣/interferon-␥) significantly increased cellular apoptosis; this increase was abolished by pretreatment with Rspo1. Rspo1 also stimulated insulin secretion in a glucose-independent fashion. We further demonstrated that the glucagon-like peptide-1 receptor agonist, exendin4 (EX4), stimulated Rspo1 mRNA transcript levels in MIN6 cells in a glucose-, time-, dose-, and PI3-kinase-dependent fashion. This effect was not limited to this ␤-cell line, as similar time-dependent increases in Rspo1 were also observed in the ␤TC ␤-cell line and mouse islets in response to EX4 treatment. Together, these studies demonstrate that Rspo1 is a novel ␤-cell growth factor and insulin secretagogue that is regulated by EX4. These findings suggest that Rspo1 and the cWnt signaling pathway may serve as a novel target to enhance ␤-cell growth and function in patients with type 2 diabetes. Type 2 diabetes mellitus (T2DM)4 represents a serious and growing epidemic that poses a major public health threat in the 21st century. The development of T2DM usually requires the presence of both insulin resistance and impaired ␤-cell function, but also involves the loss of ␤-cells (1). Moreover, type 1 diabetes mellitus (T1DM) is characterized by the autoimmunemediated destruction of ␤-cells. Therefore, novel therapeutic approaches that enhance ␤-cell mass expansion, as well as ␤-cell function, represent an exciting arsenal against diabetes.Wnt signaling has been demonstrate to play important roles in development as well as in the pathogenesis of a variety of diseases, including diabetes (2). Activation of this pathway requires interaction between a secreted glycoprotein, Wnt, and a seven transmembrane receptor protein, Frizzled (Frz). There are at least three distinct intracellular Wnt pathways, including, most notably, the canonical Wnt (cWnt) cascade that leads to changes in intracellular ␤-catenin levels and is thought to be involved in cell fate specification and proliferation. ␤-catenin is normally phosphorylated and targeted for proteolysis by a complex of proteins, including adenomatosis polyposis coli (APC), axin and the serine/threonine kinase glycogen synthase kinase-3 ␤ (GSK3␤) (Fig. 1A). cWnt activation of the Frz and low density lipoprotein receptor-related protein (LRP) co-receptors results in dissociation of this degradation complex, permitting entry of ␤-c...

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Section: Discussionsupporting

confidence: 50%

R-spondin-1 Is a Novel β-Cell Growth Factor and Insulin Secretagogue

Wong

Yeung

Schultz

et al. 2010

Journal of Biological Chemistry

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“…Under these conditions, the PI3K/Akt pathway downstream of Jak2 is downregulated, thus reducing the inhibitory phosphorylation of GSK3β. According to previous reports, GSK3β is also activated by etoposide or ceramide, which may be mediated indirectly through PP2A activation [14], [22], [23]. In accordance with this, etoposide or doxorubicin reduced the inhibitory phosphorylation of GSK3β, which was inhibited by the PP2A inhibitor okadaic acid (Fig.…”

Section: Discussionsupporting

confidence: 84%

“…5A), thus suggesting that molecular mechanisms other than that regulating cell cycle progression may also play an important role in activation of apoptotic signaling downstream of GSK3β. In this regard, GSK3β has been implicated in direct or indirect activation of Bax, caspase-2, and caspase-3 leading to apoptosis [14], [23], [24]. These possibilities as well as the mechanisms involved in GSK3β activation under DNA damage stress need to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Stress and Inhibition of Jak2-V617F Cause Its Degradation and Synergistically Induce Apoptosis through Activation of GSK3β

Nagao

Oshikawa

et al. 2011

PLoS ONE

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The cytoplasmic tyrosine kinase Jak2 plays a crucial role in cytokine receptor signaling in hematopoietic cells. The activated Jak2-V617F mutant is present in most cases of BCR/ABL-negative myeloproliferative neoplasms and constitutively activates downstream signals from homodimeric cytokine receptors, such as the erythropoietin receptor (EpoR). Here we examine the effects of DNA damage stress on Jak2 or Jak2-V617F and on induction of apoptosis in hematopoietic cells. Etoposide or doxorubicin dose-dependently decreased the expression level of Jak2 in UT7 or 32D cells expressing EpoR in the absence of Epo and that of exogenously expressed Jak2-V617F in UT7 cells when cotreated with the Jak2 inhibitor JakI-1 or AG490. Studies with pharmacological inhibitors and genetic manipulations further showed that downregulation of the PI3K/Akt pathway leading to the activation of GSK3β may be involved in downregulation of Jak2 or Jak2-V617F as well as in synergistic induction of Bax activation and apoptosis. The downregulation of Jak2 was inhibited by the proteasome inhibitor MG132 or by expression of both of loss-of-function mutants of c-Cbl and Cbl-b, E3 ubiquitin ligases which facilitated ubiquitination of Jak2-V617F when co-expressed in 293T cells. The pan-caspase inhibitor Boc-d-fmk also inhibited the Jak2 downregulation as well as appearance of a 100-kDa fragment that contained the N-terminal portion of Jak2 in response to DNA damage. Together, these data suggest that DNA damage stress with simultaneous inhibition of the kinase activity causes degradation of Jak2 or Jak2-V617F by caspase cleavage and proteasomal degradation through GSK3β activation, which is closely involved in synergistic induction of apoptosis in hematopoietic cells.

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“…There are two GSK3 isoforms in mammalians that are encoded by distinct genes: GSK3a and GSK3b. GSK3b has differential roles in the regulation of transcriptional activation and apoptosis (Park et al, 2009;Yun et al, 2009). GSK3b is recognized as much potential tumor suppressor as GSK3 phosphorylated pro-oncogenic molecules such as c-Jun, c-Myc, CREB, CCND1, and b-catenin.…”

Section: Discussionmentioning

confidence: 99%

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

Varol

Konac

Onen

et al. 2014

DNA and Cell Biology

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The epigenetic suppression of Wnt antagonists (sFRPs, DKKs, and WIF-1) causes the activation of both β-catenin and target genes, which play an important role in cell proliferation, metastasis, and angiogenesis. This study is aimed to investigate, on transcriptional and protein levels, the synergic effects of unaccompanied and/or combined use of 5-aza-2'-deoxycytidine (DAC, 5-aza-dC), trichostatin A (TSA), and gemcitabine+cisplatin chemotherapeutic agents on the apoptotic pathway of human bladder cancer cell line T24. The anti-tumor effects of gemcitabine (0-500 nM), cisplatin (0-10 μM), DAC (10 μM), and TSA (300 nM) alone and/or together on T24 cells were determined by WST-1. ELISA method was used to analyze the effects of unaccompanied and combined use of gemcitabine+cisplatin, DAC, and TSA on cell proliferation and determine the cytotoxic and apoptotic dosages at the level of H3 histone acetylation. Methylation-specific PCR was used to evaluate methylation profiles of Wnt antagonist gene (WIF-1). In the case of unaccompanied and/or combined use of specified drugs, the variations in the expression levels of CTNNB1, GSK3β, c-MYC, CCND1, CASP-3, CASP-8, CASP-9, BCL2L1, and WIF-1 genes were determined by quantitative real-time PCR. Our results indicate that through inhibition of DNA methylation, expression of β-catenin and Wnt antagonist re-activation and expressions of canonical Wnt/β-catenin pathway target genes, c-myc and cyclin D1 (CCND1), have decreased. In addition, DAC, TSA, and gemcitabine+cisplatin combination caused an increase in GSK3β mRNA levels, which in turn significantly decreased CCND1 mRNA levels. Moreover, BCL2L1, an anti-apoptotic gene, was downregulated significantly. Meanwhile, both CASP-3 mRNA and active caspase-3 protein levels increased with respect to control (p<0.01). The results revealed that use of quadruplicate gemcitabine+cisplatin+DAC+TSA combination led to a reduced inhibition of canonical Wnt/β-catenin pathway and reduced cell proliferation. Our findings may offer a new approach to consider in the treatment of bladder cancer.

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Glycogen synthase kinase-3β regulates etoposide-induced apoptosis via Bcl-2 mediated caspase-3 activation in C3H10T1/2 cells

Cited by 21 publications

References 20 publications

R-spondin-1 Is a Novel β-Cell Growth Factor and Insulin Secretagogue

R-spondin-1 Is a Novel β-Cell Growth Factor and Insulin Secretagogue

DNA Damage Stress and Inhibition of Jak2-V617F Cause Its Degradation and Synergistically Induce Apoptosis through Activation of GSK3β

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

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