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)

Apoptosis is a significant factor in cardiac dysfunction and graft failure in cardiac rejection. In this study, we examined potential signaling molecules responsible for caspase 3 activation in a model of acute cardiac allograft rejection. The roles of reactive oxygen species (ROS) and nitric oxide (NO) were determined in untreated allografts and allograft recipients treated with either cyclosporine (CsA), alpha-phenyl-t-butylnitrone (PBN, a spin-trapping agent), vitamin C (VitC), Mn(III)tetrakis (1-methyl-4-pyridyl)porphyrin); MnTmPyP, a superoxide dismutase (SOD) mimetic), or L-(1-iminoethyl)lysine) (L-NIL), an inhibitor of inducible NO synthase (iNOS) enzyme activity. Graft tissue was taken for measuring superoxide radical production, Western blotting, and direct measurement of caspase 3 activity. Activation of caspase 3 in untreated allografts was revealed by the appearance of cleaved caspase 3 from pro-caspase 3 by Western blotting and functional caspase 3 catalytic activity. CsA or PBN inhibited iNOS expression and caspase 3 activity. VitC and MnTmPyP did not alter iNOS expression or decrease NO levels but did inhibit caspase 3 activity. In contrast, L-NIL completely inhibited the increase in NO production without altering iNOS expression and inhibited caspase 3 activity. The prevention of TUNEL staining by MnTmPyP and L-NIL confirmed downstream effects of superoxide and NO on apoptosis. These studies indicate that both superoxide and NO (precursors of peroxynitrite formation) play a significant role in caspase 3 activation in cardiac allograft rejection.
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PMID:Reactive oxygen and reactive nitrogen as signaling molecules for caspase 3 activation in acute cardiac transplant rejection. 1832 72

Human TFPI-2 is an extracellular matrix-associated Kunitz-type serine proteinase inhibitor. We previously demonstrated that a human fibrosarcoma cell line, HT-1080, does not express TFPI-2, but genetic restoration of TFPI-2 expression in these cells markedly inhibited their growth and metastasis in vivo. In the present study, either full-length recombinant TFPI-2, or its mutated first Kunitz-type domain (R24K KD1), were offered to HT-1080 cells, and the degree of apoptosis assessed by nuclear fragmentation, ethidium bromide and acridine orange staining, fluorescence activated cell sorting, immunoblotting and gene expression profiling. R24K KD1 induced apoptosis in 69% of HT-1080 cells in a 48 h period compared to 39% for TFPI-2, while a KD1 preparation lacking a reactive site arginine/lysine residue (R24Q KD1) produced only an 18% apoptosis rate, suggesting that the observed apoptosis was related to proteinase inhibition. Immunoblotting experiments indicated increased caspase 3 and 9 activation, up-regulation of pro-apoptotic Bax and suppression of anti-apoptotic Bcl-2 protein. Finally, microarray analyses of R24K KD1-treated cells indicated elevated expression of several pro-apoptotic genes and under-expression of anti-apoptotic genes. Collectively, our results demonstrate that treatment of HT-1080 cells exogenously with either TFPI-2 or R24K KD1 activates caspase-mediated, pro-apoptotic signaling pathways resulting in apoptosis.
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PMID:Human tissue factor pathway inhibitor-2 induces caspase-mediated apoptosis in a human fibrosarcoma cell line. 1840 18

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of beta-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin contribute to the anti-apoptotic effects of ghrelin.
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PMID:Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. 1854 46

Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof(-/-) embryos in vitro. Mof(-/-) embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof(-/-) cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.
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PMID:Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture. 1854 69

Here we have delineated regions of the retinoid X receptor alpha (RXRalpha) that are required for rexinoid (RXR agonist)-induced growth inhibition and apoptosis. Stable over-expression of RXRalpha in DT40 B lymphoma cells dramatically increased sensitivity to rexinoid-induced growth inhibition. By contrast, DT40 cells that over-expressed RXRalpha with a deletion of either the A/B or DNA binding domain (C domain) were resistant. We confirmed the importance of C domain integrity by point-mutating Cys(135) to Ser (C135S) to disrupt zinc-finger formation. Point mutating RXR Lys(201) to Thr and Arg(202) to Ala (KTRA) impairs RXR homodimer formation and does not affect RXR heterodimerization. When these mutated RXRs were over-expressed in DT40 cells, they failed to increase sensitivity to rexinoid. Over-expression did sensitize to growth inhibition by RAR and PPARgamma agonists. Over-expression of C135S mutated RXRalpha did not sensitize to RAR and PPARgamma agonists. Inhibitors of caspase-3 and/or caspase-9 blocked rexinoid-induced apoptosis, and activations of these caspases correlated with the ability of RXR mutants to induce cell death. These data show that the A/B and C domains of RXR and the ability of RXR to form homodimers are required for rexinoid-driven growth inhibition, caspase activation and subsequent apoptosis.
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PMID:Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis. 1876 6

Recently, we reported stimulatory effect of ghrelin alone and in combination with growth hormone (GH) on estradiol secretion, aromatase activity in parallel with inhibitory effect on cell apoptosis. The aim of this study was to analyze the expression of the functional ghrelin receptor (GHS-R type 1a) and the effect of GH on GHSR-1a expression in cultured whole porcine follicles. Using RT-PCR and Western Blots, we demonstrated the presence of GHSR-1a in prepubertal pig ovary and found no influence of GH on either GHSR-1a protein levels or mRNA expression. Additionally, to show if, noted previously by us action of ghrelin on ovarian follicular function is dependent of its binding to GHSR-1a, we used an antagonist of the ghrelin receptor, (D-Lys-3)-GHRP-6. In cultures treated together ghrelin and (D-Lys-3)-GHRP-6, estradiol secretion, aromatase activity and cell proliferation returned to control levels. Inhibitory action on caspase-3 activity was not reversed by a selective antagonist of GHSR-1a. In conclusion, results of the present data clearly showed: (1) the presence of GHSR-1a in prepubertal pig ovary and found no influence of GH on GHSR-1a protein levels and mRNA expression, and (2) ghrelin effect on estradiol secretion, aromatase activity and cell proliferation dependent of its binding to GHSR-1a, while the effect on cellular apoptosis was independent of its binding to GHSR-1a.
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PMID:Expression of ghrelin receptor, GHSR-1a, and its functional role in the porcine ovarian follicles. 1880 47

5-Azacytidine (5-aza-CR) is a DNA-hypomethylating antineoplastic agent used because of its inhibitory activity on DNA methyltransferases. Today, it is approved as an epigenetically active drug therapy for treatment of myelodysplastic disorders, with a contraindication as to pre-existing liver diseases. Because the mechanism of its hepatotoxicity is still unknown, we investigated the pharmacodynamic properties of 5-aza-CR with regard to death receptor/ligand-induced apoptosis and the mode of execution of cell death. In a time- and concentration-dependent manner, primary murine, human hepatocytes and HepG2 cells exposed to 5-aza-CR became highly sensitive toward cell death induced by CD95L, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, or TNF. Cell death was characterized as apoptotic by membrane blebbing, chromatin condensation, and exposure of phosphatidylserine on the outer membrane. Neither 5-aza-2'-deoxycytidine nor the common DNA methyltransferase inhibitors S-(5'-adenosyl)-L-homocysteine or RG 108 showed any significant effects under these conditions. Despite the complete protection of HepG2 by high concentrations of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (z-VAD-fmk), effector caspase-3/7 activity was completely abolished at approximately a 20-fold lower concentration of z-VAD-fmk. Under these conditions, the serine protease inhibitors N,alpha-tosyl-L-phenylalanine chloromethyl ketone, N,p-tosyl-L-lysine chloromethyl ketone, and 4-(2-aminoethyl)-benzenesulfonyl fluoride, respectively, conferred protection against death receptor ligands. We conclude that this caspase-independent apoptosis is executed by a yet-unidentified serine protease.
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PMID:Sensitization by 5-azacytidine toward death receptor-induced hepatic apoptosis. 1882 27

Nucleophosmin/B23, a major nucleolar phosphoprotein, is overexpressed in actively proliferating cells. In this study, we demonstrate that B23 exclusively localizes in the nucleolus, whereas ATP depletion results in the redistribution of B23 throughout the whole nucleus and destabilizes B23 via caspase-3 mediated cleavage. Interestingly, ATP binding precedes PI(3,4,5)P(3) binding at lysine 263 and ATP binding mutants fail to restore the anti-apoptotic functions of B23 in PC12 cells. Thus, the ATP-B23 interaction is required for the stability of the B23 protein and regulates cell survival, confining B23 within the nucleolus in PC12 cells.
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PMID:Disruption of ATP binding destabilizes NPM/B23 and inhibits anti-apoptotic function. 1912 73

Synthetic phosphothioated (PTO) oligodeoxynucleotide (ODN) sequences are commonly used for a variety of applications that benefit from nuclease protection. The PTO modification is implemented mainly in antisense ODN, but also in ODN that were shown to activate members of the toll-like receptor (TLR) family such as TLR3 (poly-I:C), TLR8 (ssRNA), and TLR9 (CpG). Neurons are routinely plated on surfaces coated with either cationic substances such as poly-L-ornithine (PLO), polyethylenimine (PEI), poly-L-lysine or ECM components such as laminin, collagen, or fibronectin. We found that PTO-ODN aimed at activating TLR9 induces a non-TLR9-specific detachment phenotype in cortical neurons plated on either laminin or PEI, but not on PLO. This phenotype was correlated with decreased viability and was partially inhibited when caspase-3 was inhibited with Ac-DEVD-CMK. This finding suggests that the use of PTO-ODN can cause nonspecific effects on cell adhesion that could compromise interpretation of data from experiments using PTO-ODN.
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PMID:Phosphothioated oligodeoxynucleotides induce nonspecific effects on neuronal cell adhesion in a growth substrate-dependent manner. 1915 68

The rosette nanotubes (RNTs) are a class of biologically inspired, self-assembling, metal-free, hydrophilic nanotubes, which hold tremendous potential as targeted drug delivery vehicles. We investigated the cell signaling events caused by lysine-functionalized RNTs (K-RNT) co-assembled with Arg-Gly-Asp-Ser-Lys-functionalized RNTs (RGDSK-RNT) for induction of inflammation and apoptosis in human adenocarcinoma (Calu-3) cells. When co-assembled in a ratio of 1:10 microM these composite RNTs (referred to as RGDSK/K-RNTs) rapidly induced phosphorylation of P38 mitogen-activated protein kinase (MAPK) within 2 min. Higher concentrations of RGDSK/K-RNTs (>10:100 microM) resulted in a P38 MAPK-dependent increase in secretion of TNF-alpha. RGDSK/K-RNTs (1:10-40:400 microM) also caused a concentration- and P38 MAPK-dependent increase in caspase-3 activity and DNA fragmentation in Calu-3 cells at 18 h of exposure. Over-expression of pro-apoptotic genes including caspase-3, BAK1, CIDEB, TP53BP2, FAS, TNF and FASLG supported pro-apoptotic behaviors of these RNTs. We conclude that RGDSK/K-RNTs induce phosphorylation of P38 MAPK, which regulate secretion of TNF-alpha, activation of caspase-3 and apoptosis in Calu-3 cells. These results suggest that the RNTs could be used as a drug to induce apoptosis in cancer cells or as a versatile platform to deliver a variety of biologically active molecules for cancer therapy.
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PMID:The role of RGD-tagged helical rosette nanotubes in the induction of inflammation and apoptosis in human lung adenocarcinoma cells through the P38 MAPK pathway. 1925 Jun 66


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