Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin exerts potent antiapoptotic effects in neuronal cells and has been suggested to promote angiogenesis. Therefore, we investigated whether insulin inhibits tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in human umbilical vein endothelial cells (HUVECs). Because insulin has been shown to stimulate the protein kinase Akt, we investigated whether activation of Akt contributes to the apoptosis-suppressive effect of insulin and characterized the downstream signaling pathway. Incubation with insulin dose-dependently prevented apoptosis induced by TNF-alpha (50 ng/mL). The extent of apoptosis suppression by insulin was similar to the effect of vascular endothelial growth factor. Pharmacological inhibition of Akt activation or overexpression of a dominant-negative Akt mutant prevented the antiapoptotic effect of insulin. Furthermore, we investigated the effect of TNF-alpha on Akt phosphorylation by Western blot analysis with the use of a phosphospecific Akt antibody. Incubation of HUVECs with TNF-alpha induced a marked dephosphorylation of Akt. Insulin counteracted this TNF-alpha-induced dephosphorylation of Akt. Furthermore, we investigated the downstream signaling events. Akt has been shown to mediate its apoptosis-suppressive effects via phosphorylation of Bad or caspase-9. However, incubation with insulin did not lead to enhanced phosphorylation of Bad at Ser 136 or Ser 112. In contrast, insulin inhibited caspase-9 activity and prevented caspase-9-induced apoptosis. Mutation of the Akt site within caspase-9 significantly reduced the apoptosis-suppressive effect of insulin. The present study demonstrates an important role for insulin-mediated Akt activation in the prevention of endothelial cell apoptosis, which may importantly contribute to cell homeostasis and the integrity of the endothelium. In endothelial cells, Akt seems to mediate its antiapoptotic effect, at least in part, via phosphorylation of caspase-9 rather than Bad.
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PMID:Insulin-mediated stimulation of protein kinase Akt: A potent survival signaling cascade for endothelial cells. 1066 36

Molecular scanning of human IRS-1 gene revealed a common polymorphism causing Gly-->Arg972 change. Diabetic and pre-diabetic carriers of Arg972 IRS-1 are characterized by low fasting levels of insulin and C-peptide. To investigate directly whether the Arg 972 IRS-1 affects human islet cells survival, we took advantage of the unique opportunity to analyze pancreatic islets isolated from three donors heterozygous for the Arg972 and six donors carrying wild-type IRS-1. Islets from carriers of Arg972 IRS-1 showed a two-fold increase in the number of apoptotic cells as compared with wild-type. IRS-1-associated PI3-kinase activity was decreased in islets from carriers of Arg972 IRS-1. Same results were reproduced in RIN rat b-cell lines stably expressing wild-type IRS-1 or Arg972 IRS-1. Using these cells, we characterized the downstream pathway by which Arg972 IRS-1 impairs b-cell survival. RIN-Arg972 cells exhibited a marked impairment in the sequential activation of PI3-kinase, Akt, and BAD as compared with RI N-WT. Impaired BAD phosphorylation resulted in increased binding to Bcl-XL instead of 14-3-3 protein, thus sequestering the Bcl-XL antiapoptotic protein to promote survival. Both caspase-9 and caspase-3 activities were increased in RIN-Arg972 cells. The results show that the common Arg972 polymorphism in IRS-1 impairs human b-cell survival and causes resistance to antiapoptotic effects of insulin by affecting the PI3-kinase/Akt survival pathway. These findings establish an important role for the insulin signaling in human b-cell survival and suggest that genetic defects in early steps of insulin signaling may contribute to b-cell failure.
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PMID:The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. 1109 86

Insulin-like growth factor-binding protein (IGFBP)-3 has been shown to potently inhibit cell proliferation in various cell systems. However, the specific mechanisms involved in the antiproliferative action of IGFBP-3 have yet to be elucidated. In the present study, we demonstrate that IGFBP-3 induces apoptosis in an insulin-like growth factor (IGF)-independent manner through the activation of caspases involved in a death receptor-mediated pathway in MCF-7 human breast cancer cells. Induction of IGFBP-3 using an ecdysone-inducible expression system inhibited DNA synthesis in an IGF-IGF receptor axis-independent fashion and resulted in the subsequent induction of apoptosis and an increase in caspase activity. Similar results were obtained when cells were transfected with GGG-IGFBP-3, an IGFBP-3 mutant unable to bind IGFs, corroborating the IGF-independent action of IGFBP-3. Additional caspase activity studies and immunoblot analyses using specific caspase substrates and/or caspase inhibitors revealed that the growth-inhibitory effect of IGFBP-3 results mainly from its induction of apoptosis (in particular, activation of caspase-8 and -7). Analyses of caspase-9 activity and release of cytochrome c into the cytosol confirmed that the mitochondria-mediated pathway is not involved. Taken together, these results show that IGFBP-3 expression leads to the induction of apoptosis through the activation of caspases involved in a death receptor-mediated pathway and that IGFBP-3 functions as a negative regulator of breast cancer cell growth, independent of the IGF-IGF receptor axis.
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PMID:Insulin-like growth factor-binding protein 3 induces caspase-dependent apoptosis through a death receptor-mediated pathway in MCF-7 human breast cancer cells. 1502 67

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.
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PMID:Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma. 1510 34

Insulin and dexamethasone are potent inhibitors of apoptosis induced by transforming growth factor-beta1 (TGF-beta) in hepatoma cells. Using FTO-2B rat hepatoma cells, we determined whether the anti-apoptotic effects of these agents result from interference within or upstream of the TGF-beta-induced caspase cascade. Activation of different initiator and effector caspases, Bax and Bcl-xL expression, mitochondrial cytochrome c release and activation of PKB/Akt were analyzed by use of synthetic caspase substrates and Western blotting, respectively. TGF-beta-induced apoptosis was characterized by release of cytochrome c from mitochondria and activation of caspases-3, -7, -8 and -9. These effects were observable as early as 8-12 h after start of treatment and increased with time of observation. Inhibition of TGF-beta-induced apoptosis by insulin and dexamethasone was paralleled by a strong reduction of caspase-3-like activity. Caspase-8 activation was almost completely suppressed by these agents, and caspase-9 activity was decreased to levels within or slightly above unstimulated control cells. In addition, cytochrome c release from mitochondria was efficiently repressed, which was associated with upregulation of Bcl-xL by dexamethasone and activation of PKB/Akt by insulin. Thus, both anti-apoptotic compounds exert their inhibitory effects through modulation of anti-apoptotic signalling pathways involved in regulation of cytochrome c release and activation of the caspase machinery.
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PMID:Insulin and dexamethasone inhibit TGF-beta-induced apoptosis of hepatoma cells upstream of the caspase activation cascade. 1538 40

Insulin significantly reduced tumor necrosis factor (TNF)-alpha-induced cleavage of procaspase-8, -9, and -3 and poly(ADP-ribose) polymerase when observed for up to 24 hours in a dose-dependent manner. Signaling pathways responsible for the inhibitory effects of insulin were investigated by using protein kinase inhibitors. Both phosphatidylinositol 3'-kinase (PI3K) and mitogen-activated protein kinase kinase pathways mediate the ability of insulin to decrease the TNF-alpha-induced cleavage of procaspase-8. In contrast, only the PI3K inhibitor reversed the effect of insulin on the TNF-alpha-induced cleavage of procaspase-9. Moreover, insulin decreased the apoptotic level induced by TNF-alpha, whereas the PI3K inhibitor enhanced it. The protein level of Apaf-1, an activator of procaspase-9, remained constant with the application of agents affecting the cleavage of procaspase-9. In examining another regulator of cleaved caspase-9, X chromosome-linked inhibitor of apoptosis protein (XIAP), we observed that TNF-alpha treatment induced fragmentation of XIAP, which was also enhanced by the PI3K inhibitor. In addition, XIAP was coimmunoprecipitated with procaspase-9. The treatment with TNF-alpha reduced the level of XIAP precipitated with procaspase-9, whereas insulin reversed this effect. Moreover, PI3K and Akt inhibitors, but not mammalian target of rapamycin inhibitor, inhibited the effect of insulin on the coprecipitation of procaspase-9 and XIAP. Our data suggest that insulin decreases the TNF-alpha-induced cleavage of procaspase-9 and subsequent apoptosis by regulating XIAP via the PI3K/Akt pathway.
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PMID:Insulin regulates cleavage of procaspase-9 via binding of X chromosome-linked inhibitor of apoptosis protein in HT-29 cells. 1560 74

Recently, we identified thioredoxin-interacting protein (TXNIP) as the most dramatically glucose-induced gene in our human islet microarray study. TXNIP is a regulator of the cellular redox state, but its role in pancreatic beta-cells and the mechanism of its regulation by glucose remain unknown. We therefore generated a stable transfected beta-cell line (INS-1) overexpressing human TXNIP and found that TXNIP overexpression induced apoptosis as assessed by Bax, Bcl2, caspase-3, and cleaved caspase-9 as well as Hoechst staining. Interestingly, islets of insulin-resistant/diabetic mice (AZIP-F1, BTBRob/ob) demonstrated elevated TXNIP expression, suggesting that TXNIP may play a role in glucotoxicity and the beta-cell loss observed under these conditions. Furthermore, we found that glucose-induced TXNIP transcription is not dependent on glucose metabolism and is mediated by a distinct carbohydrate response element (ChoRE) in the human TXNIP promoter consisting of a perfect nonpalindromic repeat of two E-boxes. Transfection studies demonstrated that this ChoRE was necessary and sufficient to confer glucose responsiveness. Thus, TXNIP is a novel proapoptotic beta-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and beta-cell apoptosis.
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PMID:Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. 1570 78

We aimed to investigate the role of phosphatidylinositol 3 (PI3)-kinase/Akt pathway on ischemic injury. Rat liver grafts were preserved in UW solution with different treatments and were compared by 1-week survival rates and morphological changes with those of the control group. PI3-kinase/Akt was significantly activated at the sites of Thr 308 and Ser 473 in the preserved grafts. Downstream target proteins, glycogen synthase kinase-3beta (GSK-3beta) and caspase-9, were inactivated. However, survival signal transduction from Akt to Bad was blocked by calcium release after activation of PI3-kinase/Akt. Significant activation of caspase-12, -3 and -7 contributed to cell apoptosis and severe ischemic injury was shown after 7 h of preservation by UW solution with insulin. Downregulation of phospho-Akt at Thr 308 and Ser 473 was due to partial inhibition of PI3-kinase/Akt pathway by LY294002. Activation of GSK-3beta and inactivation of caspase-12 and Bad could be found in the LY294002 groups in which the liver grafts showed less ischemic injury. Higher 1-week survival rates in the heparin, LY294002, and glucagon groups confirmed the dysregulation of the pathway. In conclusion, PI3-kinase/Akt pathway was dysregulated and contributed to ischemic injury during preservation. Heparin and LY294002 could improve graft viability by maintaining calcium homeostasis during preservation.
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PMID:The influence of phosphatidylinositol 3-kinase/Akt pathway on the ischemic injury during rat liver graft preservation. 1588 30

American ginseng root displays the ability to achieve glucose homeostasis both experimentally and clinically but the unknown mechanism used by ginseng to achieve its therapeutic effects on diabetes limits its application. Disruption in the insulin secretion of pancreatic beta cells is considered the major cause of diabetes. A mitochondrial protein, uncoupling protein-2 (UCP-2) has been found to play a critical role in insulin synthesis and beta cell survival. Our preliminary studies found that the extracts of American ginseng inhibit UCP-2 expression which may contribute to the ability of ginseng protecting beta cell death and improving insulin synthesis. Therefore, we hypothesized that ginseng extracts suppress UCP-2 in the mitochondria of pancreatic beta cells, promoting insulin synthesis and anti-apoptosis (a programmed cell-death mechanism). To test the hypothesis, the serum-deprived quiescent beta cells were cultured with or without interleukin-1beta (IL-1beta), (200 pg ml(-1), a cytokine to induce beta cell apoptosis) and water extracts of American ginseng (25 mug per 5 mul administered to wells of 0.5 ml culture) for 24 h. We evaluated effects of ginseng on UCP-2 expression, insulin production, anti-/pro-apoptotic factors Bcl-2/caspase-9 expression and cellular ATP levels. We found that ginseng suppresses UCP-2, down-regulates caspase-9 while increasing ATP and insulin production/secretion and up-regulates Bcl-2, reducing apoptosis. These findings suggest that stimulation of insulin production and prevention of beta cell loss by American ginseng extracts can occur via the inhibition of mitochondrial UCP-2, resulting in increase in the ATP level and the anti-apoptotic factor Bcl-2, while down-regulation of pro-apoptotic factor caspase-9 occurs, lowering the occurrence of apoptosis, which support the hypothesis.
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PMID:American ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. 1695 21

The mechanisms involved in regulating mammary cell turnover during the pregnancy-lactation cycle in dairy cows are unclear. The objective of present experiment was to describe expression of genes encoding proteins known to be involved in pathways regulating mammary cell proliferation, apoptosis, differentiation, cell survival, and tissue remodeling. Mammary gland biopsies were taken 7 times during the pregnancy-lactation cycle of 10 dairy cows, and samples were analyzed by immunohistochemistry and real-time PCR. Cell proliferation was greatest during the dry period and apoptosis was high in early dry period and early lactation. Based on Fas (tumor necrosis factor receptor superfamily member 6), Fas ligand, and caspase-3, caspase-8, and caspase-9 gene expression, no indication was found of a stage-dependent shift between the extrinsic and intrinsic pathways leading to apoptosis. Gene expression of microsomal glutathione S-transferase (mGST) did not vary significantly, whereas B-cell leukemia/lymphoma 2 (Bcl-2) and BCL2-associated X protein (Bax) gene expression was greatest during the dry period and early lactation and coincided with high cell turnover. Gene expression of early response genes c-Fos, c-Jun, and c-Myc correlated to neither rate of cell proliferation nor plasma concentration of insulin-like growth factor (IGF)-I and insulin. Gene expression of nuclear factor of kappa light chain gene enhancer in B-cells (NFkappaB) and NFkappaB inhibitor alpha was greatest in the periparturient period, and NFkappaB gene expression coincided with an anticipated need for cell survival factors. Expression of transforming growth factor beta (TGF-beta) receptor 1 and 2 mRNA was greatest in early lactation, whereas TGF-beta1 did not vary significant during the pregnancy-lactation cycle. Even though our results on the TGF-beta system did not comply with other studies, the gene expression pattern of the TGF-beta receptors indicates a role in regulating apoptosis in early lactation. Signal transducer and activator of transcription 5 (STAT5) gene expression was high in the periparturient period, which suggests a role for STAT5 in regulation of mammary cell proliferation and differentiation in dairy cows. Expression of tissue-plasminogen activator, plasminogen activator inhibitor-1, and IGF binding protein 5 genes was greatest in early lactation, suggesting a role for IGF binding protein 5 in coordinating regulation of apoptosis and tissue remodeling.
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PMID:Cellular mechanisms in regulating mammary cell turnover during lactation and dry period in dairy cows. 1848 54


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