Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have presently determined the effect of inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) on the occurrence of apoptosis in insulin-producing cells. The ADP-ribosylation activities of intact cells were decreased by incubation of RINm5F cells for 16 h with the PARP inhibitors nicotinamide (NA) (20-50 mM) or 3-aminobenzamide (3-ABA) (10 mM). Exposure to 20-50 mM NA or 10 mM 3-ABA both resulted in massive apoptosis in RINm5F cells. A 24 h exposure to 50 mM nicotinamide induced apoptosis in fetal but not adult rat islet cells. In addition, exposure of RINm5F cells to 50 mM NA for 12-24 h induced the appearance of the 85 kDa proteolytic PARP fragment, indicating activation of the ICE-like protease caspase-3. Incubation with 20-50 mM NA did not induce any consistent effects upon transcription factor NF-kappaB activity, demonstrating that this pathway is not involved in induction of apoptosis by NA. It is concluded that in insulin-producing cells with a high mitotic rate, inhibition of ADP-ribosylation--and consequently of auto-modification and release of PARP bound to DNA strand breaks--leads to activation of programmed cell death.
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PMID:Nicotinamide-induced apoptosis in insulin producing cells is associated with cleavage of poly(ADP-ribose) polymerase. 970 78

Peroxynitrite, a cytotoxic oxidant formed in the reaction of superoxide and nitric oxide is known to cause programmed cell death. However, the mechanisms of peroxynitrite-induced apoptosis are poorly defined. The present study was designed to characterize the molecular mechanisms by which peroxynitrite induces apoptosis in HL-60 cells, with special emphasis on the role of caspases. Peroxynitrite induced the activation of apopain/caspase-3, but not ICE/caspase-1 as measured by the cleavage of fluorogenic peptides. Considering the short half-life of peroxynitrite and the kinetics of caspase-3 activation (starting 3-4 h after peroxynitrite treatment), the enzyme is not likely to become activated directly by the oxidant. Caspase-3 activation proved to be essential for DNA fragmentation, because pretreatment of the cells with the specific tetrapeptide inhibitor DEVD-fmk completely blocked peroxynitrite-induced DNA fragmentation. Peroxynitrite-induced cytotoxicity was also significantly altered by the inhibition of caspase-3, whereas phosphatidylserine exposure was unaffected by DEVD-fmk treatment. Because many of the effects of peroxynitrite are mediated by poly(ADP-ribose) synthetase (PARS) activation, we have also investigated the effect of PARS-inhibition on peroxynitrite-induced apoptosis. We have found that PARS-inhibition modulates peroxynitrite-induced apoptotic DNA fragmentation in the HL-60 cells. The effect of the PARS inhibitors, 3-aminobenzamide and 5-iodo-6-amino-1,2-benzopyrone were dependent on the concentration of peroxynitrite used. While PARS-inhibition resulted in increased DNA-fragmentation at low doses (15 microM) of peroxynitrite, a decreased DNA-fragmentation was found at high doses (60 microM) of peroxynitrite. PARS inhibition negatively affected viability as determined by flow cytometry. These data demonstrate the crucial role of caspase-3 in mediating apoptotic DNA fragmentation in HL-60 cells exposed to peroxynitrite.
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PMID:Crucial role of apopain in the peroxynitrite-induced apoptotic DNA fragmentation. 987 May 61

We investigated the mechanism of 3-morpholinosyndnomine (SIN-1) neurotoxicity in nearly pure neuronal cultures. In a simple saline solution, SIN-1 neurotoxicity was found to be mediated by peroxynitrite and independent of glutamate receptor activation [Y. Zhang & P.A. Rosenberg (2002) Eur. J. Neurosci, 16, 1015-1024]. To further study the mechanism of peroxynitrite toxicity to neurons we investigated the role of caspases and poly (ADP-ribose) polymerase (PARP) in this model system. Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-cmk), a specific caspase-1 inhibitor, completely blocked neurotoxicity as well as ATP depletion induced by SIN-1. However, a caspase-3 inhibitor and a pan-caspase inhibitor were both without effect. These results suggested that the protection of Ac-YVAD-cmk might not be due to its inhibition of caspase-1. Indeed, Western blot analysis and assay of caspase activity indicated that caspase activation was not involved in SIN-1 toxicity. Ac-YVAD-cmk also completely blocked in vitro protein nitration induced by SIN-1 or peroxynitrite, suggesting that Ac-YVAD-cmk may interact with peroxynitrite directly. Similarly, although activation of PARP is thought to be a major cause of peroxynitrite-induced ATP depletion, and two PARP inhibitors, 1,5-dihydroxyisoquinoline (DHQ) and 3-aminobenzamide (3-AB), completely prevented ATP depletion and neurotoxicity induced by SIN-1, SIN-1 did not increase poly (ADP-ribosyl)ation and PARP activity. Furthermore, DHQ and 3-AB completely prevented in vitro protein nitration induced by peroxynitrite, indicating that DHQ and 3-AB directly interact with peroxynitrite. Taken together, these results suggest that in the model system used here peroxynitrite neurotoxicity is independent of caspase and PARP activation, and therefore implicate a novel mechanism.
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PMID:Caspase-1 and poly (ADP-ribose) polymerase inhibitors may protect against peroxynitrite-induced neurotoxicity independent of their enzyme inhibitor activity. 1537 93