Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin and insulin receptor substrate 1 (IRS-1) are capable of protecting liver cells from apoptosis induced by transforming growth factor-beta1 (TGF-beta). The Ras/mitogen-activated protein kinase (MAP kinase) and the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathways are both activated upon insulin stimulation and can protect against apoptosis under certain circumstances. We investigated which of these pathways is responsible for the protective effect of insulin on TGF-beta-induced apoptosis. An activated Ras, although elicited a strong mitogenic effect, could not protect Hep3B cells from TGF-beta-induced apoptosis. Furthermore, PD98059, a selective inhibitor of MEK, did not suppress the antiapoptotic effect of insulin. In contrast, the PI 3-kinase inhibitor, LY294002, efficiently blocked the effect of insulin. Protection against TGF-beta-induced apoptosis conferred by PI 3-kinase was further verified by stable transfection of an activated PI 3-kinase. Downstream targets of PI 3-kinase involved in this protection was further investigated. An activated Akt mimicked the antiapoptotic effect of insulin, whereas a dominant-negative Akt inhibited such effect. However, rapamycin, the p70S6 kinase inhibitor, had no effect on the protectivity of insulin against TGF-beta-induced apoptosis, suggesting that the antiapoptotic target of PI 3-kinase/Akt pathway is independent or lies upstream of the p70S6 kinase. The mechanism by which PI 3-kinase/Akt pathway interferes with the apoptotic signaling of TGF-beta was explored. Activation of PI 3-kinase did not lead to a suppression of Smad hetero-oligomerization or nuclear translocation but blocked TGF-beta-induced caspase-3-like activity. In summary, the PI 3-kinase/Akt pathway, but not the Ras/MAP kinase pathway, protects against TGF-beta-induced apoptosis by inhibiting a step downstream of Smad but upstream of caspase-3.
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PMID:Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. 978 39

In the critically ill, glucocorticoids induce myopathy, combining profound protein catabolism and mild myotubular death. Insulin-like growth factors (IGFs) inhibit muscle catabolism through activation of phosphatidylinositol 3-kinase (PI3K). Using rat L6 myoblasts, we show that IGF-I also acts through PI3K to inhibit apoptosis induced by hyperosmolar metabolic stress with 300 mM mannitol. We find that the glucocorticoid dexamethasone inhibits this antiapoptotic effect of IGF-I by impairing PI3K signaling. Dexamethasone induces overexpression of the PI3K subunit p85alpha, which, in turn, competes with the complete PI3K heterodimer for binding at insulin receptor substrate-1, inhibiting PI3K activation. Dexamethasone blocks IGF-I-induced phosphorylation of Akt, a PI3K-dependent process. Increased cellular p85alpha abundance, induced by either 10 microM dexamethasone or transient transfection with a plasmid coding for p85alpha, significantly inhibits IGF-I rescue from apoptosis induced by mannitol, as indicated by both loss of cell viability and increased activity of caspase-3 by fluorogenic assay. Conversely, constitutively active PI3K inhibits death induced by mannitol, even in the presence of dexamethasone. These findings may have particular relevance in the pathogenesis of acute steroid myopathy in critical illness, in which catabolic glucocorticoid effects combine with acute metabolic stressors, including sepsis, fasting, and chemical denervation.
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PMID:Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis. 1091 83

Apoptosis of cardiac muscle cells contributes to the development of cardiomyopathy. Recent studies showed that insulin-like growth factor I (IGF-I) inhibits apoptosis of cardiac muscle cells and improves myocardial function in experimental heart failure. This study was carried out to elucidate the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the anti-apoptotic actions of IGF-I in cardiomyocytes and to explore whether expression of constitutively active PI 3-kinase can inhibit apoptosis in cardiomyocytes. Apoptosis of primary cardiomyocytes was induced by doxorubicin treatment and serum withdrawal. Transduction of cardiomyocytes with constitutively active PI 3-kinase specifically lead to serine phosphorylation of Akt, whereas phosphorylation of IGF-I receptor, IRS1/2 and p44/42 mitogen-activated protein kinase were not increased. In the cardiomyocytes transduced with constitutively active PI 3-kinase, activation of the pro-apoptotic caspase 3 was attenuated and fragmentation of DNA was reduced. Preincubating cells with PI 3-kinase inhibitor LY294002 was associated with loss of anti-apoptotic actions of IGF-I and PI 3-kinase. Neither IGF-I nor constitutively active PI 3-kinase lead to serine phosphorylation of Bad, suggesting that the anti-apoptotic effects of PI 3-kinase are not mediated through Bad phosphorylation in cardiac muscle cells. To determine whether activation of caspase 3 is sufficient to induce apoptosis in cardiomyocytes, an engineered TAT-caspase 3 protein was introduced to cardiomyocytes. Significant reduction of cell viability occurred in the cardiomyocytes transduced with active caspase 3, indicating that activation of caspase 3 is sufficient to cause cardiomyocyte death. These findings indicate the existence of an IGF-I receptor-PI 3-kinase-caspase 3 pathway in cardiomyocytes that plays an important role in the anti-apoptotic actions of IGF-I in heart. Moreover, these data suggest that modulation of PI 3-kinase activities may represent a potential therapeutic strategy to counteract the occurrence of apoptosis in cardiomyopathy.
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PMID:Expression of constitutively active phosphatidylinositol 3-kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells. 1100 72

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-1 (IGF-1) and insulin are known to prevent apoptosis. The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. Five hours after serum withdrawal, cells already began to undergo apoptosis. At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. The biochemical basis of the defect in anti-apoptosis was not dependent on phosphorylation of mitogen-activated protein kinase; whereas phosphoinositide 3-kinase activity was decreased by 30% in IRS-1 KO cells. Akt phosphorylation was slightly reduced in these cells. Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms.
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PMID:Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. 1208

Chronic ethanol consumption can cause sustained hepatocellular injury and inhibit the subsequent regenerative response. These effects of ethanol may be mediated by impaired hepatocyte survival mechanisms. The present study examines the effects of ethanol on survival signaling in the intact liver. Adult Long Evans rats were maintained on ethanol-containing or isocaloric control liquid diets for 8 weeks, after which the livers were harvested to measure mRNA levels, protein expression, and kinase or phosphatase activity related to survival or proapoptosis mechanisms. Chronic ethanol exposure resulted in increased hepatocellular labeling for activated caspase 3 and nuclear DNA damage as demonstrated using the TUNEL assay. These effects of ethanol were associated with reduced levels of tyrosyl phosphorylated (PY) IRS-1 and PI3 kinase, Akt kinase, and Erk MAPK activities and increased levels of phosphatase tensin homologue deleted on chromosome 10 (PTEN) mRNA, protein, and phosphatase activity in liver tissue. In vitro experiments demonstrated that ethanol increases PTEN expression and function in hepatocytes. However, analysis of signaling cascade pertinent to PTEN function revealed increased levels of nuclear p53 and Fas receptor mRNA but without corresponding increases in GSK-3 activity or activated BAD. Although fork-head transcription factor levels were increased in ethanol-exposed livers, virtually all of the fork-head protein detected by Western blot analysis was localized within the cytosolic fraction. In conclusion, chronic ethanol exposure impairs survival mechanisms in the liver because of inhibition of signaling through PI3 kinase and Akt and increased levels of PTEN. However, uncoupling of the signaling cascade downstream of PTEN that mediates apoptosis may account for the relatively modest degrees of ongoing cell loss observed in livers of chronic ethanol-fed rats.
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PMID:Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. 1293 97

Insulin receptor substrate (IRS)-2 has been implicated in the promotion of beta-cell survival. Here we tested the hypothesis that the novel analog [LysB3, GluB29] insulin (insulin glulisine, IG) might mediate an enhanced beta-cell protective effect due to its unique property of preferential IRS-2 phosphorylation. We assessed IRS activation by IG and its anti-apoptotic activity against cytokines or palmitic acid in comparison to insulin, insulin analogs, and insulin-like growth factor (IGF)-I using INS-1 cells. IG induced a prominent IRS-2 activation without significant IRS-1 stimulation. The marked cytokine- and fatty acid-induced apoptosis was strongly (55-60%) inhibited by IG both at the level of caspase 3 activation and nucleosomal release, with only 15% inhibition of apoptosis by regular insulin. At 1nM, insulin, insulin aspart, and insulin lispro were much less effective compared to IG. In conclusion, the prominent anti-apoptotic activity of insulin glulisine might serve to counteract autoimmune- and lipotoxicity-induced beta-cell destruction.
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PMID:[LysB3, GluB29] insulin: a novel insulin analog with enhanced beta-cell protective action. 1455 Feb 82

Muscle proteolysis from catabolic conditions, including chronic kidney disease, requires coordinated activation of both the apoptotic and ATP-ubiquitin-proteasome systems (Ub-P'some), including upregulation of components of the Ub-P'some system. Activation of the apoptotic system is required because caspase-3 initially cleaves myofibrils, yielding substrates for the Ub-P'some system plus a characteristic 14-kD actin fragment. The authors studied insulin deficiency, a model of accelerated muscle atrophy, to understand how regulation of the apoptotic and the Ub-P'some systems could be coordinated. As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. Coordinated atrogin-1/MAFbx expression is required as a critical factor for Ub-P'some system-dependent muscle proteolysis in diabetes and other catabolic states. The mechanism that regulates atrogin-1/MAFbx expression is unknown. Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased. When PI3K activity is low, both apoptotic and Ub-P'some pathways are activated coordinately to cause muscle proteolysis. This mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.
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PMID:Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. 1515 64

Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.
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PMID:IGF-I prevents glutamate-induced motor neuron programmed cell death. 1519 97

Muscle atrophy is a prominent feature of chronic kidney disease (CKD) and is frequent in other catabolic conditions. Results from animal models of these conditions as well as patients indicate that atrophy is mainly owing to accelerated muscle proteolysis in the ubiquitin-proteasome (Ub-P'some) proteolytic system. The Ub-P'some system, however, rapidly degrades actin or myosin but cannot breakdown actomyosin or myofibrils. Consequently, another protease must initially cleave the complex structure of muscle. We identified caspase-3 as an initial and potentially rate-limiting proteolytic step that cleaves actomyosin/myofibrils to produce substrates degraded by the Ub-P'some system. In rodent models of CKD and other catabolic conditions, we find that caspase-3 is activated and cleaves actomyosin to actin, myosin and their fragments. This initial proteolytic step in muscle leaves a characteristic footprint, a 14-kDa actin band, providing a potential diagnostic tool to detect muscle catabolism. We also found that stimulation of caspase-3 activity depends on inhibition of IRS-1-associated phosphatidylinositol 3-kinase (PI3K) activity; inhibiting PI3K in muscle cells also leads to expression of a critical E3-ubiquitin-conjugating enzyme involved in muscle protein breakdown: atrogin-1/MAFbx. Thus, protein breakdown by caspase-3 and the ubiquitin-proteasome system in muscle are stimulated by the same signal: a low PI3K activity. These responses could yield therapeutic strategies to block muscle atrophy.
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PMID:Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions. 1573 69


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