Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3(-/-) MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3(-/-) MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50alpha and p55alpha was induced in response to LIF in SOCS3(-/-) MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3(-/-) MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3(-/-) cells. Not only the up-regulation of p50alpha and p55alpha but also the repression of cyclin D1 and Bcl-2 in SOCS3(-/-) MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance.
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PMID:Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. 1702 85

Interleukin-6 (IL-6) is a major regulator of the acute phase reaction in the liver and is thought to mediate protective effects in response to hepatotoxins. In this study, the influence of bile acids on IL-6 signal transduction was analyzed. It was shown that hydrophobic bile acids such as glycochenodeoxycholate (GCDC) inhibited IL-6-induced tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver. This inhibition was accompanied by GCDC-mediated downregulation of glycoprotein (gp) 130 expression, whereas gp130 and suppressor of cytokine signaling 3 messenger RNA and gp80 protein levels remained unaffected. The GCDC-induced downregulation of gp130 protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of caspase-3 or caspase-8 activity. Accordingly, treatment of cell extracts with active recombinant caspase-3 led to a decay of immunoreactive gp130. Moreover, activation of caspases by CD95 ligand or hyperosmotic stress also resulted in a downregulation of gp130 levels. This indicates that caspase activation antagonizes IL-6 signaling by decay of gp130 levels. However, caspase inhibition did not prevent GCDC-dependent inhibition of IL-6-induced STAT3 activation, which turned out to be at least partially sensitive to suppression of p38(MAPK) activation. In conclusion, hydrophobic bile acids compromise IL-6 signaling through both a caspase-mediated downregulation of gp130 and a p38(MAPK)-dependent inhibition of STAT3 phosphorylation. This may contribute to bile acid-induced hepatotoxicity in cholestasis through counteracting the known hepatoprotective effects of IL-6.
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PMID:Bile acids inhibit interleukin-6 signaling via gp130 receptor-dependent and -independent pathways in rat liver. 1705 37

We investigated the molecular mechanisms of the anti-apoptotic properties of granulocyte-colony stimulating factor (G-CSF) on neurons and whether G-CSF affects glial cell survival following focal cerebral ischemia in rats. Sprague-Dawley rats were subjected to a transient 90 min middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Rats were treated with either a single dose of G-CSF (50 microg/kg, s.c.) at the onset of reperfusion or G-CSF (50 microg/kg body weight, s.c.) was administered starting at the onset of reperfusion and followed by the administration of the same dose per day for an additional 2 days. Brains were harvested either 24 h, 72 h or 2 weeks after reperfusion for assays of infarct volume, immunohistological studies and Western blot analysis for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Pim-1, bcl-2, Bax, cytochrome c, cellular inhibitor of apoptosis protein 2 (cIAP2), and cleaved caspase-3 levels. G-CSF significantly reduced infarct volume and ameliorated the early neurological outcome. G-CSF treatment significantly up-regulated pSTAT3, Pim-1, bcl-2 expression, and down-regulated cytochrome c release to the cytosol, Bax translocation to the mitochondria, and cleaved caspase-3 levels in neurons. The activation of the STAT3 pathway was accompanied by increased cIAP2 expression in glial cells. After MCAO, G-CSF treatment increased both neuronal and glial survival by effecting different anti-apoptotic pathways which reflects the multifactorial actions of this drug. These changes were associated with remarkable improvement in tissue preservation and behavioral outcome.
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PMID:Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. 1708 35

IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2(c) and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G(2)-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by approximately 50% as measured by [(3)H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3'-deoxy-3'-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.
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PMID:IL-22-mediated tumor growth reduction correlates with inhibition of ERK1/2 and AKT phosphorylation and induction of cell cycle arrest in the G2-M phase. 1711 5

Increased polyamine synthesis has been associated with proliferation and progression of breast cancer, and thus, is a potential target for anti-cancer therapy. Polyamine depletion by DFMO has been shown to decrease pulmonary and bone metastasis from human breast cancer cell xenografts. Following these observations, this study was designed to test the effects of DFMO on in vitro and in vivo features of the highly invasive and metastatic 4T1 murine mammary cancer cells. DFMO inhibited proliferation, caused G1-S arrest, and suppressed in vitro invasiveness of 4T1 cells. In contrast to our previous findings with MDA-MB-435 cells, DFMO did not affect the activation of STAT3, JNK, and ERK, but decreased phosphorylation of p38. DFMO did not alter the expression of Twist. DFMO delayed the orthotopic growth of 4T1 xenografts in association with suppressed putrescine and spermidine levels but increased levels of spermine. DFMO did not affect pulmonary metastasis when primary tumors of control and DFMO-treated mice were matched for size. Interestingly, DFMO reduced Ki-67 expression only in the primary tumors but did not affect its expression in the metastatic tumors in the lung. Cleaved caspase-3 expression was not affected by DFMO in either the primary tumors or pulmonary metastasis. In summary, DFMO treatment markedly inhibited in vitro proliferation and invasiveness of 4T1 cells and retarded the growth of orthotopic xenografts in mice. The failure of DFMO to inhibit pulmonary metastasis in this system appears to be due, at least in part, to its lack of anti-proliferative effect at the metastatic sites.
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PMID:Effects of polyamine depletion by alpha-difluoromethylornithine on in vitro and in vivo biological properties of 4T1 murine mammary cancer cells. 1714 92

Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.
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PMID:Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. 1716 50

Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1-deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun-NH2-terminal kinase activation after I/R in normal mice but not in CT-1-null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti-CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1-null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6-deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1-null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP.
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PMID:Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning. 1717 16

IFN regulatory factor (IRF)-2(-/-) mice are significantly more resistant to LPS challenge than wild-type littermates, and this was correlated with increased numbers of apoptotic Kupffer cells. To assess the generality of this observation, and to understand the role of IRF-2 in apoptosis, responses of peritoneal macrophages from IRF-2(+/+) and IRF-2(-/-) mice to apoptotic stimuli, including the fungal metabolite, gliotoxin, were compared. IRF-2(-/-) macrophages exhibited a consistently higher incidence of apoptosis that failed to correlate with caspase-3/7 activity. Using microarray gene expression profiling of liver RNA samples derived from IRF-2(+/+) and IRF-2(-/-) mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF-2(-/-) mice, including Stat3, which has been reported to regulate apoptosis. Compared with IRF-2(+/+) macrophages, STAT3alpha mRNA was up-regulated constitutively or after gliotoxin treatment of IRF-2(-/-) macrophages, whereas STAT3beta mRNA was down-regulated. Phospho-Y705-STAT3, phospho-S727-STAT1, and phospho-p38 protein levels were also significantly higher in IRF-2(-/-) than control macrophages. Activation of the STAT signaling pathway has been shown to elicit expression of CASP1 and apoptosis. IRF-2(-/-) macrophages exhibited increased basal and gliotoxin-induced caspase-1 mRNA expression and enhanced caspase-1 activity. Pharmacologic inhibition of STAT3 and caspase-1 abolished gliotoxin-induced apoptosis in IRF-2(-/-) macrophages. A novel IFN-stimulated response element, identified within the murine promoter of Casp1, was determined to be functional by EMSA and supershift analysis. Collectively, these data support the hypothesis that IRF-2 acts as a transcriptional repressor of Casp1, and that the absence of IRF-2 renders macrophages more sensitive to apoptotic stimuli in a caspase-1-dependent process.
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PMID:IFN regulatory factor-2 regulates macrophage apoptosis through a STAT1/3- and caspase-1-dependent mechanism. 1733 57

Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia-ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 microg/kg, subcutaneous) was administered 1 h after HI and given on four subsequent days (five total injections). Animals were euthanized 24 h, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase-3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury and that this may occur in part by an inhibition of apoptotic cell death.
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PMID:Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia-ischemia in rats. 1735 43

The molecular mechanisms of apoptosis caused by IFN-gamma (interferon gamma)/LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells) have not been studied in detail. The present study was undertaken to gain insights into the signaling pathways involved in apoptosis induced by IFN-gamma/LIGHT in hepatocellular carcinoma (HCC) cell lines. Cell proliferation assay, flow cytometry, Western blotting, gene transfer and RNA interference were used in this study. LIGHT enhanced IFN-gamma-mediated apoptosis in Hep3B cells. IFN-gamma/LIGHT-induced apoptosis was inhibited by blocking peptides to the lymphotoxin beta receptor (LT-beta R), and not by the herpes virus entry mediator (HVEM). Expression of LT-beta R remained unchanged after cytokine treatments. IFN-gamma/LIGHT treatment resulted in the down-regulation of Bcl-XL and the activation of caspase-9 and caspase-3 as well as the decrease of phosphorylation of STAT3. HepG2 and SMMC-7721 cells, which showed high levels of endogenous Bcl-XL, displayed resistance to IFN-gamma/LIGHT-induced apoptosis. Overexpression of Bcl-XL in Hep3B cells increased the resistance to IFN-gamma/LIGHT induced apoptosis while the down-regulation of Bcl-XL in HepG2 and SMMC-7721 cells by RNA interference decreased the resistance. Our study provides important mechanistic insights into IFN-gamma/LIGHT- induced apoptosis in HCC cells and may help to select better therapeutic strategies for certain cancers with distinct Bcl-XL expression.
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PMID:Expression level of Bcl-XL critically affects sensitivity of hepatocellular carcinoma cells to LIGHT-enhanced and interferon-gamma-induced apoptosis. 1739 46


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