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

Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
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PMID:Neurons undergo apoptosis in animal and cell culture models of diabetes. 1052 3

Ewing's sarcoma family of tumors (ESFTs) affects patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. These tumors contain a characteristic translocation, t(11;22), that produces a unique fusion protein, EWS/FLI-1. EWS/FLI-1 transforms mouse fibroblasts; this transformation requires intact EWS and FLI-1 domains as well as the insulin-like growth factor-I receptor (IGF-IR). The IGF-IR is a well-described transmembrane tyrosine kinase receptor that modulates transformation, cell growth, and survival. IGF-IR survival signaling is mediated through the downstream activation of phosphoinositide 3-OH kinase (PI 3-K) and Akt. Apoptosis, programmed cell death, progresses from a central death signal to a caspase cascade, including activation of caspase-3. Because the IGF-IR has been shown to play a role in the transformation and growth of ESFTs, we wanted to determine the role of downstream molecules in the cellular response to doxorubicin treatment. Doxorubicin increased caspase-3 activity in two ESFT cell lines, TC-32 and TC-71. Concomitant treatment of the doxorubicin-treated cells with IGF-I reduced caspase-3 activity 8-fold in TC-32 and 4-fold in TC-71. To determine whether PI 3-K has a role in IGF-I-mediated survival in ESFTs, PI 3-K was then inhibited with wortmannin and LY294002. Doxorubicin treatment reduced cell number and enhanced apoptosis in PI 3-K inhibited cells compared with noninhibited cells. Akt, a serine/threonine kinase activated downstream of PI 3-K, was investigated to determine whether its constitutive activation would render ESFT cells more resistant to doxorubicin. A constitutively activated Akt was stably transfected into ESFT and those cells with high levels of expression demonstrated increased resistance to doxorubicin-induced caspase-3 activation. These results indicate that ESFT cell lines use an IGF-IR initiated signaling pathway through PI 3-K and Akt for survival when treated with doxorubicin.
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PMID:Phosphoinositide 3-hydroxide kinase blockade enhances apoptosis in the Ewing's sarcoma family of tumors. 1058 94

The type I insulin-like growth factor receptor (IGF-IR) is important for mitogenesis, transformation, and survival of tumor cells. The current study examines the effect of IGF-IR expression and activation on apoptosis in SHEP human neuroblastoma cells. SHEP cells undergo apoptosis which is prevented by IGF-I addition or overexpression of the IGF-IR (SHEP/IGF-IR cells). High mannitol treatment activates caspase-3 by 1 h in SHEP cells while caspase-3 activation is delayed by 3 h in SHEP/IGF-IR cells. Transfection with Bcl-2 (SHEP/Bcl-2 cells) prevents serum withdrawal and mannitol induced apoptosis and caspase-3 activation. Mannitol induces mitochondrial membrane depolarization in both SHEP and SHEP/IGF-IR cells. IGF-IR activation or overexpression of Bcl-2 in SHEP cells prevents mitochondrial membrane depolarization. Collectively, these results suggest that IGF-IR or Bcl-2 overexpression in neuroblastoma cells promotes cell survival by preventing mitochondrial membrane depolarization and caspase-3 activation, ultimately leading to increased tumor growth.
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PMID:IGF-I receptor activation and BCL-2 overexpression prevent early apoptotic events in human neuroblastoma. 1088 10

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

Recently we have shown that adult rat retinal ganglion cells (RGCs) die by apoptosis following optic nerve (ON) transection, activating caspase-3. In the present study, we report that caspase-9, known to be an important activator of caspase-3, becomes activated in the axotomized adult rat retina as revealed by immunoblot analysis and protease activity assays. Reduction of caspase-9 activity by repeated intraocular injection of specific inhibitors significantly prevented RGC death. Caspase-9 activity was effectively blocked by inhibitor treatment and by application of IGF-I and BDNF, neurotrophic factors which have been shown to be highly neuroprotective in this model. Taken together, our data suggest that caspase-9 plays a critical role in apoptosis induction in axotomized RGCs in vivo and is regulated under treatment with growth and survival factors. Thus, providing more insight into the mechanisms underlying neuronal death and survival following trauma might serve as a basis to improve future therapeutic strategies preventing or at least reducing the severe consequences of neuronal injury.
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PMID:Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. 1114 16

The involvement of p53, Bax, cytochrome C and CPP-32 (caspase-3) in the molecular mechanism ofTGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC) was examined. Laser scanning cytometry (LSC) was applied for the quantitative analysis of expression and distribution of examined apoptosis-related proteins in the cytoplasmic (Cf) and nuclear (Nf) area. Maximal pixel of fluorescence (MP) parameter corresponding to aggregation of molecules in the cell was also measured. Confocal and immunoelectron microscopy were used as a complementary methods. Apoptosis induced by TGF-beta1 (2 ng/ml) was associated with the increase of Bax MP observed within 60 min. after cytokine administration, indicating aggregation of Bax in the cell. Immunoelectron microscopy revealed Bax aggregation on mitochondrial membranes, rough endoplasmic reticulum, Golgi apparatus, cytoskeleton, nuclear envelope and inside of nucleus. The accumulation of Bax in the nucleus was confirmed by compartmental Bax analysis, showing the increase of cell number with elevated Bax Nf in 2 hr after TGF-beta1 administration to the culture. The redistribution of Bax within the cell was dependent on its activation occurring by the cleavage at N-terminal epitope and exposure of BH3 domain. Bax aggregation on organelles was completely abolished by prolactin or IGF-I. TGF-beta1 increased p53 MP, evidently after 4 hr of cell culture exposure to this cytokine. p53 was accumulated first of all in the nucleus, which was shown by significant increase of p53 Nf/Cf ratio and increase of p53-related nuclear fluorescence on confocal images. TGF-beta1 decreased cytochrome C MP, which corresponded to its release from mitochondria and dissipation in the cytosol. It was accompanied by the increase of CPP-32 MP and concentration of 89 kDa product of PARP degradation in the nucleus. In conclusion, TGF-beta1 triggers apoptosis in MEC through mitochondrial pathway involving: activation and translocation of Bax to mitochondrial membranes, release of cytochrome C from mitochondria, activation of CPP-32 and degradation of its substrate - PARP in the nucleus. Activation and subcellular redistribution of Bax is inhibited by lactogenic hormones: prolactin and IGF-I.
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PMID:Molecular mechanism of TGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC). 1193 68

Glutamate toxicity is a major contributor to death of oligodendroglia in diverse CNS disorders. The goal of these studies was to investigate the mechanisms of glutamate toxicity and trophic factor protection of the immature pro-oligodendroblast (pro-OL). Glutamate induced time- and dose-dependent DNA fragmentation and caspase-3 activation in pro-OLs. IGF-I or NT-3, but not CNTF, prevented apoptosis of pro-OLs by 24 h via a PI3-kinase-dependent pathway; however, only IGF-I protected pro-OLs from glutamate toxicity through 48 h. Long-term protection of pro-OLs by IGF-I was correlated with sustained activation of Akt while NT-3 activation of Akt was transient. The differential ability of IGF-I and NT-3 to maintain Akt activation was due to differences in receptor activation and stability. In the presence of NT-3, TrkC phosphorylation and protein expression decreased significantly while activation of the IGF-IR was maintained in the pro-OLs in the presence of IGF-I.
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PMID:Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis. 1213 23

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, beta-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Histological analysis indicated reduced numbers of alveolar end buds, with decreased ductal branching. Transgenic dams produced IGFBP-5 in their milk at concentrations similar to those achieved at the end of normal lactation. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. BrdU labelling was decreased, whereas DNA ladders were increased in transgenic animals on day 1 of lactation. On day 2 postpartum, the epithelial invasion of the mammary fat pad was clearly impaired in transgenic animals. The concentrations of the pro-apoptotic molecule caspase-3 and of plasmin were both increased in transgenic animals whilst the concentrations of 2 prosurvival molecules Bcl-2 and Bcl-x(L)were both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I we examined IGF receptor phosphorylation and Akt phosphorylation and showed that both were inhibited. We attempted to "rescue" the transgenic phenotype by using growth hormone to increase endogenous IGF-I concentrations or by implanting minipumps delivering an IGF-1 analogue, R(3)-IGF-1, which binds weakly to IGFBP-5. Growth hormone treatment failed to affect mammary development suggesting that increased concentrations of endogenous IGF-1 are insufficient to overcome the high concentrations of IGFBP-5 produced by these transgenic animals. In contrast mammary development (gland weight and DNA content) was normalised by R3-IGF-I although milk production was only partially restored. This is the first demonstration that over-expression of IGFBP-5 can lead to; impaired mammary development, increased expression of the pro-apoptotic molecule caspase-3, increased plasmin generation and decreased expression of pro-survival molecules of the Bcl-2 family. It clearly demonstrates that IGF-I is an important developmental/survival factor for the mammary gland and, furthermore, this cell death programme may be utilised in a wide variety of tissues.
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PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. 1222 11

The importance of the mitochondria in UV-induced apoptosis has become increasingly apparent. Following DNA damage cytochrome c and other pro-apoptotic factors are released from the mitochondria, allowing for formation of the apoptosome and subsequent cleavage and activation of caspase-9. Active caspase-9 then activates downstream caspases-3 and/or -7, which in turn cleave poly(ADP)-ribose polymerase (PARP) and other down-stream targets, resulting in apoptosis. In an effort to understand the mechanisms of Akt-mediated cell survival in breast cancer, we studied the effects of insulin-like growth factor (IGF)-I treatment on UV-treated MCF-7 human breast cancer cells. Apoptosis was induced in MCF-7 cells after UV treatment, as measured by caspase-7 and PARP cleavage, and IGF-I co-treatment protected against this response. Surprisingly caspase-9 cleavage was unchanged with UV and/or IGF-I treatment. Using MCF-7 cells overexpressing caspase-3 we have shown that resistance of caspase-9 to cleavage was not altered by the expression of caspase-3. Furthermore, overexpression of caspase-9 did not enhance PARP or caspase-7 cleavage after UV treatment. Because caspase-8 was activated with UV treatment alone, we believe that UV-induced apoptosis in MCF-7 cells occurs independently of cytochrome c and caspase-9, supporting the existence of a cytoplasmic inhibitor of cytochrome c in MCF-7 cells. We anticipate that such inhibitors may be overexpressed in cancer cells, allowing for treatment resistance.
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PMID:UV-induced apoptosis is mediated independent of caspase-9 in MCF-7 cells: a model for cytochrome c resistance. 1295 16

Apoptosis of vascular smooth muscle cells (VSMCs) is of importance in the development of diabetic angiopathy. Our aim was to evaluate the effect of insulin and IGF-I on apoptosis in VSMCs. Rat aortic VSMCs were used and apoptosis was induced by serum starvation. As apoptotic markers we measured caspase-3 activity, histone-associated DNA fragments by ELISA and nuclear morphology by DAPI (4',6-diamidino-2-phenylindole) staining. Phosphorylation of IGF-I receptors was evaluated by Western blot. Serum starvation had increased caspase-3 activity even after 3 h. The highest activity was found after 3-12 h. IGF-I 10(-9 )M inhibited serum starvation-induced caspase-3 activity with a maximal effect after 12 h. When studied after starvation for 12 h, significant inhibitory effects on caspase-3 were found at IGF-I concentrations of 10(-8)-10(-7) M (P<0.01) and at an insulin concentration of 10(-6 )M (P<0.01). DNA fragmentation was detected by ELISA after 24 h and chromatin condensation and nuclear fragmentation by DAPI staining after 24 and 48 h respectively. IGF-I dose-dependently reduced apoptosis evaluated by ELISA, reaching a maximal effect at 10(-9) M. Insulin reduced apoptosis but the effect was weaker and a higher concentration was needed. IGF-I (10(-8 )M) and insulin at a very high concentration (10(-6) M) phosphorylated IGF-I receptors. Taken together, IGF-I and insulin have antiapoptotic effects on VSMCs but the effect of insulin is only found at high unphysiological concentration.
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PMID:IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells. 1459 78


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