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

Conventional photodynamic therapy (PDT) utilizes light-absorbing compounds that have anti-cancer activity upon visible light irradiation. PDT has also been utilized for the treatment of certain immune conditions. To further understand the action of PDT upon immune cells, DBA/2 mouse thymocytes were treated with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) and/or an apoptosis-inducing anti-Fas (APO-1, CD95) monoclonal antibody. Nanomolar levels of BPD-MA in combination with nonthermal visible light irradiation rapidly induced apoptosis as gauged by DNA fragmentation assays. Thymocytes were modestly more sensitive to PDT-induced apoptosis than mature splenic T cells. BPD-MA and light or the anti-Fas antibody decreased CD4(+)CD8(+) cell numbers while relatively sparing CD4(-)CD8(-), CD4(+)CD8(-), and CD4(-)CD8(+) thymocytes. In combination, anti-Fas antibody and PDT augmented activity levels of the apoptosis-related protease caspase-3, cleavage of the caspase-3 substrate poly(ADP) polymerase, and the proportion of cells exhibiting DNA fragmentation and further impacted CD4(+)CD8(+) thymocyte survival. Although CD4(+)CD8(+) thymocytes had the greatest sensitivity to photodynamic depletion, BPD-MA was taken up by the other major thymocyte subsets with equal or greater avidity. Since CD4(+)CD8(+) thymocytes are selectively impacted by PDT and anti-Fas antibody can act in concert with PDT to further cytotoxicity, thymocytes may be useful for the identification of factors that govern immune cell susceptibility to this form of phototherapy.
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PMID:Selective depletion of a thymocyte subset in vitro with an immunomodulatory photosensitizer. 1022 10

The Deleted in Colorectal Cancer gene (DCC) encodes a cell surface receptor that belongs to the Ig superfamily. Inactivation of the DCC gene has been implicated in human tumor progression. However, little is known about the biological function of the DCC protein. In the present study, we demonstrated that expression of DCC activated caspase-3 and programmed cell death, or induced G2/M cell cycle arrest in tumor cells. In some cell lines, apoptosis was evident within 24 h of DCC expression. Timing of the appearance of apoptotic cells coincided with that of the cleavage of poly (ADP-ribose) polymerase, a substrate of caspase-3. Expression of the apoptosis inhibitory gene Bcl-2 was not able to abrogate the DCC-induced apoptosis. In the G2/M cycle arrest cells, cdk1 activity was inhibited. Our results suggest that the DCC protein may transduce signals resulting in activation of caspases or inhibition of Cdk1. These data provide a possible mechanism by which DCC suppresses tumorigenesis.
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PMID:Induction of apoptosis and G2/M cell cycle arrest by DCC. 1034 49

Tumor necrosis factor-alpha (TNFalpha) may play a role in at least some of the neuronal death that occurs following brain insults or in neurodegenerative diseases. It is therefore important to characterize the mechanism underlying apoptosis induced by TNFalpha in neuronal cells and to identify factors capable of protecting neurons from this death. In the present study, we characterized the apoptotic effect of TNFalpha in PC12 cells, a model system commonly used for studying neuronal apoptosis, and examined the role of Bcl-2 and caspases in this process. We show that TNFalpha induces apoptosis in both naive and primed PC12 cells. The TNFalpha-induced apoptosis was inhibited by nerve growth factor (NGF) but not by insulin. These findings suggest that the apoptotic effect of TNFalpha can be inhibited by trophic factors and that the survival-promoting effect of NGF is mediated by a specific pathway not shared by all tyrosine kinase receptors. The effect of Bcl-2 on TNFalpha-induced apoptosis was examined in PC12 cells overexpressing Bcl-2. These cells were resistant to TNFalpha-induced apoptosis, suggesting that the apoptotic effect of TNFalpha in PC12 cells is mediated via a pathway controlled by Bcl-2. Examination of the role of caspase-3 like activity in TNFalpha-induced apoptosis showed that caspase-3-like proteases are activated, and their substrate, poly (ADP-ribose) polymerase, is cleaved following TNFalpha treatment. In addition, the broad-spectrum inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was found to inhibit the TNFalpha-induced apoptosis of PC12 cells. These results suggest that caspases are activated following TNFalpha treatment and are needed for TNFalpha-induced apoptosis in PC12 cells.
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PMID:Nerve growth factor inhibits apoptosis induced by tumor necrosis factor in PC12 cells. 1034 57

Oxidative stress may be a common mechanism underlying various forms of cell death, including necrosis and apoptosis. The authors have reported previously that the cupric nitrilotriacetate (Cu-NTA), a renal carcinogen, induces oxidative DNA damage and apoptosis in HL-60 human leukemia cells (Ma, Y., et al. Free Radic. Biol Med. 25:568-575; 1998). The focus of this investigation was to examine the possible pathway of the apoptosis induced by Cu-NTA. Results of the present study demonstrated that after exposure of HL-60 cells to Cu-NTA, an increase in lipid hydroperoxide and loss of mitochondrial membrane potential (deltaphim) were observed, followed by the increase in cytosolic cytochrome c that was released from the mitochondria. These events proceeded and triggered the activation of caspase-3 (CPP32/apopain/Yama), resulting in the degradation of poly (ADP-ribose) polymerase and DNA fragmentation. The antioxidants, N-acetylcysteine and glutathione, protected the loss of deltaphim and blocked the apoptosis induced by Cu-NTA. In addition, Ac-DEVD-CHO, a specific inhibitor of caspase-3, inhibited Cu-NTA-induced apoptosis. These results suggested that Cu-NTA-induced apoptosis in HL-60 cells was, at least in part, triggered by free radical-induced lipid peroxidation of membrane, which induced the release of cytochrome c from mitochondria and activation of caspase-3.
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PMID:Cupric nitrilotriacetate-induced apoptosis in HL-60 cells association with lipid peroxidation, release of cytochrome C from mitochondria, and activation of caspase-3. 1044 40

Since caspase members have been identified as effectors of apoptosis, the role of CPP32/caspase-3 was further explored in cultured neurons from the embryonic rat forebrain submitted to a 6-h hypoxia which has previously been shown to induce apoptotic death within four days after reoxygenation, whereas a shorter aggression (i.e., for 3 h) leads by the same time to an increased number of living neurons, suggesting that sublethal hypoxia may promote neurogenesis. Neuronal expression of the active cleavage product of CPP32 (CPP32 p20) increased specifically after hypoxia for 6 h to finally reach 985% over control normoxic values at 96 h post-insult, while a 3-h hypoxia triggered the inducible stress protein HSP70 that has been shown to inhibit caspase-3. Proteolytic activity of caspase-3 was progressively stimulated by lethal hypoxia, as reflected by the degradation of two selective substrates, including poly (ADP-ribose) polymerase (PARP). Caspase-3 activity was blocked specifically and dose-dependently by the peptide inhibitor, DEVD-CHO, that reduced the number of apoptotic cells and prevented the hypoxia-induced decrease in cell viability, including when given 24 h post-insult. Interestingly, in these conditions, the inhibitory compounds enhanced the number of mitotic neurons. These data emphasize the critical role of caspase-3 in neuronal injury consecutive to hypoxia. Whereas caspase inhibitors may provide benefit over a broad therapeutic window, they might allow developing neurons to complete their cell cycle initiated in response to stress, as it is the case for sublethal hypoxia.
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PMID:CPP32/CASPASE-3-like proteases in hypoxia-induced apoptosis in developing brain neurons. 1052 77

Amyloid beta protein (Abeta) has been thought to participate in the neurodegeneration associated with Alzheimer's disease. We here report on caspase-3 activation by Abeta-treatment of cultured neurons. Treatment of rat primary cortical culture with Abeta 25-35, an active fragment of Abeta, induced neuronal death as determined by a decrease in neuron-specific microtubule-associated protein 2 (MAP2)-like immunoreactivity and by the release of cellular lactate dehydrogenase (LDH). Abeta 25-35 also induced elevation of caspase-3-like Ac-DEVD-MCA cleavage activity in advance of neuronal death with similar concentration-dependency for neuronal death. Inhibitor sensitivity of the Abeta-induced proteolytic activity was similar to that of human recombinant caspase-3. Cleavage of pro-caspase-3 and cleavage of its endogenous substrates, poly (ADP-ribose) polymerase (PARP) and alpha-fodrin, were produced by Abeta-treatment. A caspase-3 inhibitor, Ac-DEVD-CHO, prevented Abeta-induced DNA fragmentation and cleavage of alpha-fodrin, but not of PARP. Caspase inhibitor of broad specificity, Z-VAD-CH(2)-DCB, additionally prevented Abeta-induced cleavage of PARP and some early loss of cell membrane integrity measured by LDH release. However, Abeta-induced condensation of nuclear chromatin and most of the late disintegration of cell membranes were not prevented in the presence of these caspase inhibitors. These results suggest that activation of both caspase-3 and caspase(s) other than caspase-3 play distinct roles in Abeta-induced apoptosis of rat cortical neurons. Furthermore, in the presence of caspase inhibitors, Abeta-induced neuronal death still occurred with different morphological features.
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PMID:Activation of caspase-3 in beta-amyloid-induced apoptosis of cultured rat cortical neurons. 1052 27

BACKGROUND: Previous studies have demonstrated the occurrence of apoptosis in cardiomyocytes in different types of cardiovascular diseases. This report provides the first evidence for the presence of vascular apoptosis in myocardial infarction induced in rats by occluding the coronary artery for 7 weeks. METHODS AND RESULTS: Apoptosis was characterized by DNA fragmentation, upregulation of caspase-3, downregulation of poly (ADP-ribose) polymerase (PARP), increased c-fos mRNA expression and caspase-3/PARP ratio in aortic vascular smooth muscle cells. The results show apoptotic changes in 10-25% of the aortic vascular cells after myocardial infarction; these alterations were prevented after treating the 3-week operated animals with an angiotensin II receptor antagonist, losartan (25 mg/kg/day; intraperitoneal) for 4 weeks. Cultured rat aortic smooth muscle cells exposed to 10 nmol/L angiotensin II for 48 hours also exhibited apoptotic changes, which were inhibited by 10 nmol/L losartan. CONCLUSIONS: These results suggest that vascular apoptosis occurs in myocardial infarction, and this may be due to an increase in the circulating levels of angiotensin II.
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PMID:Prevention of Vascular Apoptosis in Myocardial Infarction by Losartan. 1068 26

Hepatitis C virus (HCV) often causes a prolonged and persistent infection which may lead to hepatocellular carcinoma. We have previously reported that the nonstructural 5A (NS5A) protein of HCV promotes cell growth [Ghosh, A.K., Steele, R., Meyer, K., Ray, R., Ray, R.B., 1999. Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. J. Gen. Virol. 80, 1179-1183]. In this study, we investigated the role of HCV NS5A (genotype 1a, strain H) in TNF-alpha induced apoptotic cell death. HepG2 cells expressing NS5A exhibited an inhibitory role in relation to TNF-alpha mediated apoptotic cell death. The NS5A protein blocked the activation of caspase-3 and inhibited proteolytic cleavage of the death substrate poly (ADP-ribose) polymerase in TNF-alpha induced cells. Together, these results suggest that HCV NS5A protein protects against TNF-alpha mediated apoptotic cell death.
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PMID:Hepatitis C virus NS5A protein protects against TNF-alpha mediated apoptotic cell death. 1086 96

Administration of methamphetamine caused significant increases in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, in poly (ADP-ribose) polymerase (PARP) cleavage, as well as in caspase-3 activity in the striata of C57BL/6J mice. In contrast, all these effects were markedly suppressed in the copper-zinc superoxide dismutase transgenic mice. These results indicate that superoxide radicals might be important factors in METH-induced cell death.
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PMID:Methamphetamine-induced apoptosis is attenuated in the striata of copper-zinc superoxide dismutase transgenic mice. 1107 1

Disulfiram is frequently used in the treatment of alcoholism. In this study, we found that CuCl(2) (1-10 microM), but not other metal ions (Fe(2+), Zn(2+), Pb(2+)), markedly potentiated disulfiram-induced cytotoxicity by 440-fold in primary astrocytes. Thus, the molecular mechanisms of the cytotoxic effects induced by the disulfiram-Cu(2+) complex were explored. The changes in morphology (nuclear condensation and apoptotic body formation) and hypodiploidy of DNA suggested that the disulfiram-Cu(2+) complex induced an apoptotic process. Our studies of the death-signaling pathway reveal that decreased mitochondrial membrane potential, increased free radical production, and depletion of non-protein-thiols (glutathione) were involved. The disulfiram-Cu(2+) complex activated c-Jun-amino-terminal kinase (JNK) and caspase-3 followed by poly (ADP-ribose) polymerase degradation in a time-dependent manner. Moreover, the cellular Cu content was markedly increased and the copper chelator bathocuproine disulfonate abolished all of these cellular events, suggesting that Cu(2+) is essential for death signaling. The antioxidants N-acetylcysteine and vitamin C also inhibited the cytotoxic effect. Thus, we conclude that the disulfiram-Cu(2+) complex induces apoptosis and perhaps necrosis at a late stage mediated by oxidative stress followed by sequential activation of JNK, caspase-3 and poly (ADP-ribose) polymerase degradation. These findings imply that the axonal degeneration and neurotoxicity observed after the chronic administration of disulfiram are perhaps, at least in part, due to the cytotoxic effect of the disulfiram-Cu(2+) complex formed endogenously.
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PMID:Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu(2+) complex. 1123 17


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