UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A fall in circulating levels of cardiac survival factor insulin-like growth factor 1 (IGF-1) contributes to cardiac aging. To better understand the role of IGF-1 in cardiac aging, we examined the influence of cardiac IGF-1 overexpression on lifespan, cardiomyocyte intracellular Ca2+ homeostasis, protein damage, apoptosis and expression of pro- and anti-apoptotic proteins in young and old mice. Mouse survival rate was constructed by the Kaplan-Meier curve. Intracellular Ca2+ was evaluated by fura-2 fluorescence. Protein damage was determined by protein carbonyl formation. Apoptosis was assessed by caspase-8 expression, caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay. Pro- and anti-apoptotic proteins including Bax, p53, pp53, Bcl2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC) and X-linked inhibitor of apoptosis protein (XIAP) were assessed by Western blot. Aging decreased plasma in IGF-1 levels, elevated myocyte resting intracellular Ca2+ levels, reduced electrically stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ decay associated with enhanced protein carbonyl formation, caspase-8 expression and caspase-3 activity in FVB mice, all of which with the exception of elevated resting intracellular Ca2+ were attenuated by IGF-1. Aging up-regulated expression of Bax, Bcl2 and ARC, down-regulated XIAP expression and did not affect p53, pp53 and Omi/HtrA2. The IGF-1 transgene attenuated or nullified aging-induced changes in Bax, Bcl2 and XIAP. Our data suggest a beneficial role for IGF-1 in aging-induced survival, cardiac intracellular Ca2+ homeostasis, protein damage and apoptosis possibly related to pro- and anti-apoptotic proteins.
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PMID:Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression. 1797 71

X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family that selectively binds and inhibits caspase-3, -7 and -9. As such, XIAP is an extremely potent suppressor of apoptosis and an attractive target for cancer treatment. Che-1 is an antiapoptotic agent involved in the control of gene transcription and cell proliferation. Recently, we showed that the checkpoint kinases ATM/ATR and checkpoint kinase 2 physically and functionally interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce transcription of p53, and Che-1 depletion strongly sensitizes tumor cells to anticancer drugs. Here we show that Che-1 activates XIAP expression in response to DNA damage. This effect is mediated by Che-1 phosphorylation and requires NF-kappaB. Notably, we found that XIAP expression is necessary for antiapoptotic activity of Che-1 and that in vivo downregulation of Che-1 by small interference RNA strongly enhanced the cytotoxicity of anticancer drugs.
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PMID:Che-1 activates XIAP expression in response to DNA damage. 1804 76

The neuronal glutamate transporter EAAC1 localizes on neuronal cell membrane and uptakes glutamate from extracellular space. This function is crucial for the termination of glutamate-mediated signaling in synapse and also for prevention of neuronal death by suppressing glutamate toxicity. However, the possible mechanism of EAAC1 in preventing neuron death had not been resolved as compared with glial glutamate transporters such as GLT-1. Recently some groups revealed its additional mechanisms in terms of neuronal protection. In this review we introduce a unique "rescue" function of EAAC1, which is independent of clearance of extracellular glutamate. We recently identified that the decreased expression of EAAC1 following nerve injury in motor neuron was observed in mouse but not in rat, and the suppression in mouse was associated with motor neuron death seen in the mouse. This phenomenon leaded us to identification of a novel mechanism underlying the neuronal protection of EAAC1. During apoptotic stimuli, a mitochondrial protein, holocytochrome-c synthetase (HCCS) translocates to outside the mitochondria, binds to, and suppresses the X-linked inhibitor of apoptosis protein (XIAP), leading to activation of caspase-3. The N-terminus of EAAC1 can bind to HCCS, which interferes with the HCCS-XIAP association, and thereby maintain XIAP activity. This unique anti-apoptotic mechanism of EAAC1 functions in rescuing motor neurons from NGF deprivation and nerve injury. These facts imply that the EAAC1 has multiple mechanisms in prevention of neuron death.
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PMID:[Multiple functions of glutamate transporter EAAC1 in motor neurons]. 1809 81

In this study, the release of mitochondrial proapoptotic intermembrane space proteins induced by exogenous C(2)-ceramide in human colon carcinoma (HT-29) cell line was investigated. HT-29 cells were treated with 12.5, 25 and 50 micromol/L C(2)-ceramide in vitro. Flow cytometer was used to detect the mitochondrial membrane potential (DeltaPhi(m)). Subcellular fractions were extracted by Mitochondrial/Cytosol Fractionation Kit after C(2)-ceramide treatment for 24 h. SDS-PAGE was used to determine the level of cytochrome c (Cyt c), high temperature requirement A2 (HtrA2) and second mitochondrial-derived activator of caspases (Smac) released from mitochondria, the expression of X-linked inhibitor of apoptosis protein (XIAP) and caspase-3 for 24 h. The results showed that DeltaPhi(m) began to decrease from 6 h after 25 and 50 micromol/L C(2)-ceramide treatment (P<0.05) and cyclosporin A (CsA) could inhibit the collapse of DeltaPhi(m) through regulating mitochondrial membrane permeability transition pore. There was no effect of C(2)-ceramide on the expression of Cyt c, HtrA2 and Smac in the total levels. 12.5, 25 and 50 micromol/L C(2)-ceramide could induce Cyt c, HtrA2 and Smac to release from mitochondria to cytosol and down-regulate the expression of XIAP (P<0.05). Also there was expression of cleaved caspase-3 with C(2)-ceramide treatment. After the treatment with caspase inhibitor, C(2)-ceramide still induced the release of Cyt c and HtrA2, but Smac did not. Therefore, C(2)-ceramide could induce apoptosis of HT-29 cells through the mitochondria pathway. The release of Cyt c, HtrA2 and Smac from mitochondria did not occur via the same mechanism, the release of Cyt c and HtrA2 was caspase-independent and the release of Smac was caspase-dependent.
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PMID:Ceramide induces release of mitochondrial proapoptotic proteins in caspase-dependent and -independent manner in HT-29 cells. 1817 93

Recent studies indicate that gossypol possesses potent antitumor activities in vitro and in vivo. The nuclear factor-kappa B (NF-kappaB) plays an important role in tumor cell growth, proliferation, invasion, and survival. In this study, we investigated the effects and the molecular mechanisms of gossypol on NF-kappaB activation and NF-kappaB-related gene expression in human leukemia U937 cells. Treatment with concentrations of gossypol greater than 10 microM resulted in significant cell cytotoxicity and DNA fragmentation, indicative of apoptosis. Treatment with 10 microM gossypol also induced caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage, and resulted in the induction of apoptosis in approximately 20% of cells as determined by annexin-V staining 24h after treatment. Furthermore, gossypol exposure decreased the DNA-binding activity of NF-kappaB in a concentration-dependent manner. Treatment with gossypol also downregulated expression of NF-kappaB-regulated gene products, including inhibitor of apoptosis protein (IAP)-1, IAP-2, and X-linked IAP. Attenuation of NF-kappaB activity by pretreatment with PDTC, an NF-kappaB nuclear translocation inhibitor, significantly induced apoptosis in the presence of gossypol. Gossypol also suppressed NF-kappaB p65 mRNA accumulation, resulting in suppression of total NF-kappaB activity. This was associated with a downregulation of Sp1-binding activity, a transcription factor controlling p65 transcription. These results suggest that gossypol-induced apoptosis partially involves suppression of NF-kappaB activity.
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PMID:Gossypol suppresses NF-kappaB activity and NF-kappaB-related gene expression in human leukemia U937 cells. 1831 60

Molecular targeting for apoptosis induction is being developed for better treatment of cancer. Downregulation of 15-lipoxygenase-1 (15-LOX-1) is linked to colorectal tumorigenesis. Re-expression of 15-LOX-1 in cancer cells by pharmaceutical agents induces apoptosis. Antitumorigenic agents can also induce apoptosis via other molecular targets. Whether restoring 15-LOX-1 expression in cancer cells is therapeutically sufficient to inhibit colonic tumorigenesis remains unknown. We tested this question using an adenoviral delivery system to express 15-LOX-1 in in vitro and in vivo models of colon cancer. We found that (i) the adenoviral vector 5/3 fiber modification enhanced 15-LOX-1 gene transduction in various colorectal cancer cell lines, (ii) the adenoviral vector delivery restored 15-LOX-1 expression and enzymatic activity to therapeutic levels in colon cancer cell lines, and (iii) 15-LOX-1 expression downregulated the expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and BcL-XL, activated caspase-3, triggered apoptosis, and inhibited cancer cell survival in vitro and the growth of colon cancer xenografts in vivo. Thus, selective molecular targeting of 15-LOX-1 expression is sufficient to re-establish apoptosis in colon cancer cells and inhibit tumorigenesis. These data provide the rationale for further development of therapeutic strategies to target 15-LOX-1 molecularly for treating colonic tumorigenesis.
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PMID:Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer. 1838 20

Inhibitors of apoptosis proteins (IAPs) are a conserved family of proteins identified in species ranging from virus, yeasts, nematodes, fishes, flies and mammals. The common structural feature is the presence of at least one Baculovirus IAP Repeat (BIR) domain. Hence, IAPs are also known as BIR-containing proteins (BIRCs). Most of them display anti-apoptotic properties when overexpressed. In drosophila, IAPs are sufficient and necessary to promote cell survival through a direct regulation of apoptotic proteases called caspases. In mammals, BIRC4/XIAP, the most studied IAP member can directly inhibit the activity of caspase-3, 7 and 9. However, this activity is not conserved in other IAPs and physiological relevancies of such anti-caspase activities are still discussed. A detailed analysis of IAP-deficient mice or derived cells, deletion experiments performed in drosophila and zebrafish, or research of protein partners have revealed the importance of IAPs in adaptive response to cellular stress, in cell proliferation, differentiation, signaling, motility and in immune response. This review discusses recent data that help understanding of cellular functions of IAPs.
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PMID:IAPs: more than just inhibitors of apoptosis proteins. 1841 36

Serotonergic 5-HT(1A) receptor signaling leading to nuclear factor-kappaB (NF-kappaB) activation appears to be critical for cell survival. Adenylyl cyclase and protein kinase A (AC/PKA) are effectors of the 5-HT(1A) receptor that are inhibited by Galpha(i) subunits. Conversely, Gbetagamma(i) subunits downstream from the 5-HT(1A) receptor participate in the activation of extracellular signal-regulated kinases (ERK1/2), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-kappaB. To model the contribution of pro- and antiapoptotic signaling cascades downstream of activated 5-HT(1A) receptor in cell survival, Chinese hamster ovarian (CHO) cells were employed that exogenously overexpress 5-HT(1A) receptors. Stimulation with the 5-HT(1A) receptor agonist 8-OH-DPAT and pharmacological agonists of AC induced PKA and protein phosphatase 2A (PP2A) activity, which in turn inhibited: Akt activity, IkappaBalpha degradation, nuclear translocation of NF-kappaB, and expression of X-linked inhibitor of apoptosis protein (XIAP/BIRC4). Pharmacological inhibition of PP2A with calyculin A potentiated Akt activity while attenuating ERK1/2 signaling via increased inhibitory phosphorylation of Raf (pSer259). In contrast, increased cAMP levels enhanced Bax translocation to the mitochondria, resulting in the release of cytochrome c, caspase-3 activation, and apoptosis induction. Our data suggest a central role of cAMP/PKA-dependent PP2A in shifting the homeostasis of intracellular signaling downstream of activated 5-HT(1A) receptor toward cell death in biological systems linked to neuropsychiatric disorders.
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PMID:Inhibition of 5-HT1A receptor-dependent cell survival by cAMP/protein kinase A: role of protein phosphatase 2A and Bax. 1845 33

The inhibitors of apoptosis (IAPs) are emerging as key proteins in the control of cell death. In this study, we evaluated the expression and subcellular distribution of the antiapoptotic protein X-linked IAP (XIAP), and its interactions with the XIAP-associated factor 1 (XAF1) in neonatal rat brain following hypoxia-ischemia (HI). HI triggered the mitochondrial release of cytochrome c, Smac/DIABLO, and caspase 3 activation. Confocal microscopy detected XIAP-specific immunofluorescence in the cytoplasm under normal condition, which exhibited a diffuse distribution at 6 h post-HI and by 12 h the majority of XIAP was redistributed into the nucleus. XIAP nuclear translocation was confirmed by subcellular fractionations and by expressing FLAG-tagged XIAP in primary cortical neurons. Over-expression of XIAP significantly reduced, whereas XIAP gene silencing further enhanced cell death, demonstrating a specific requirement of cytoplasmic XIAP for cell survival. An elevated level of cytosolic XIAP was also evident under the conditions of neuroprotection by fibroblast growth factor-1. XAF1 expression was increased temporally and there was increased nuclear co-localization with XIAP in hypoxic-ischemic cells. XIAP co-immunoprecipitated > 9-fold XAF1 protein concurrent with decreased association with caspases 9 and 3. This is evidenced by the enhanced caspase 3 activity and neuronal death. Our findings implicate XIAP nuclear translocation in neuronal death and point to a novel mechanism in the regulation of hypoxic-ischemic brain injury.
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PMID:Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain. 1848

X-linked inhibitor of apoptosis protein (XIAP) inhibits apoptosis mainly through inhibition of caspase-9 and executioner caspases of -3 and -7. The inhibition of the former protease is implemented through the bacculoviral inhibitory repeat-3 (Bir3) domain, while the inhibition of the latter is accomplished by the interaction of the linker region located between the Bir1 and the Bir2 domains with their active sites. Both modes of inhibition are antagonized by SMAC, which is released from mitochondria during the initiation of the intrinsic apoptosis pathway. Although the mechanism of SMAC interference in Bir3 inhibition of caspase-9 is clearly established, the mechanism by which SMAC interferes with the inhibition of the executioner caspases by XIAP remains largely unknown. To address this issue, we performed a limited proteolysis of glutathione S-transferase (GST)-tagged XIAP-Bir2 by trypsin in the presence and in the absence of SMAC peptide. Under these conditions, the proteolysis of the linker region was diminished considerably. Furthermore, the rate of association of caspase-3 and -7 with XIAP in the presence of the SMAC peptide was reduced drastically, suggesting that SMAC peptide restricts the exposure of the linker region. A limited proteolysis of caspase-7 in the presence of GST-Bir2 and GST-NBir3 (the Bir3 domain of human NAIP) as negative controls was also performed. Matrix-assisted laser desorption/ionization time-of-flight analysis of the fragments revealed the identity of protected sites, suggesting that the Bir2 domain makes numerous contacts with the large subunit of caspase-7. These, combined with the results from Far-Western experiments, strongly suggest that the groove for the inhibitor(s)-of-apoptosis-protein-binding motif on the Bir2 favors binding to the N-terminus of the large subunit rather than to the small subunit of caspase-7. Our results further show that the active-site pocket of caspase-7 is first occupied by the linker region, followed by the interaction of the N-terminus of the enzyme with the SMAC-binding site of the Bir2 domain.
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PMID:A mechanistic insight into SMAC peptide interference with XIAP-Bir2 inhibition of executioner caspases. 1861 10

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