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)

Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.
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PMID:Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival. 1554 73

In the present study we have studied the effect of resveratrol in signal transduction mechanisms leading to apoptosis in 3T3 fibroblasts when exposed to 4-hydroxynonenal (HNE). In order to gain insight into the mechanisms of apoptotic response by HNE, we followed MAP kinase and caspase activation pathways; HNE induced early activation of JNK and p38 proteins but downregulated the basal activity of ERK (1/2). We were also able to demonstrate HNE-induced release of cytochrome c from mitochondria, caspase-9, and caspase-3 activation. Resveratrol effectively prevented HNE-induced JNK and caspase activation, and hence apoptosis. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with resveratrol. Moreover, Nrf2 downregulation by HNE could also be blocked by resveratrol. Overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicates a role for JNK-c-Jun/AP-1 pathway. In light of the JNK-dependent induction of c-Jun/AP-1 activation and the protective role of resveratrol, these data may show a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation. In this respect, resveratrol acting through MAP kinase pathways and specifically on JNK could have a role other than acting as an antioxidant-quenching reactive oxygen intermediate.
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PMID:Resveratrol protects against 4-hydroxynonenal-induced apoptosis by blocking JNK and c-JUN/AP-1 signaling. 1632 78

Bis(2-hydroxybenzylidene)acetone is a potent inducer of the phase 2 response through the Keap1-Nrf2-ARE pathway. This double Michael reaction acceptor reacts directly with Keap1, the sensor protein for inducers, leading to enhanced transcription of phase 2 genes and protection against oxidant and electrophile toxicities. In our efforts to identify potent chemoprotective agents, we found that in rapidly growing murine leukemia cells (L1210) low concentrations (in the submicromolar range) of bis(2-hydroxybenzylidene)acetone markedly increased the activities of NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) and glutathione reductase, and the levels of total glutathione, three markers of the phase 2 response. In contrast, at high concentrations (in the micromolar range) the same compound caused G2/M cell cycle arrest and apoptosis. Importantly, a mutant L1210 cell line (Y8), selected for resistance to deoxyadenosine and lacking expression of p53 protein, was considerably more sensitive to the apoptotic effects of bis(2-hydroxybenzylidene)acetone. When caspase activities were evaluated in cell-free extracts prepared from treated wild type or mutant L1210 cells, the activities of caspase-3, the terminal caspase in the cascade leading to apoptosis, and caspase-10 were found to be markedly elevated. The activities of other caspases measured, caspase-1, -6 and -8, were not appreciably affected. Thus, both induction of the phase 2 response and p53-independent, caspase-3-mediated apoptosis could act cooperatively in chemoprotection. The concentration-dependent differential effects on these two pathways should be carefully considered in mechanistic explanations and strategic designs.
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PMID:Bis(2-hydroxybenzylidene)acetone, a potent inducer of the phase 2 response, causes apoptosis in mouse leukemia cells through a p53-independent, caspase-mediated pathway. 1651 63

Diphenylarsinic acid (DPAsV) is a degradation product of chemical warfare agents, over which there has been a public outcry in the Kamisu Area of Ibaraki Prefecture in Japan. In this study, we investigated the cytotoxicity of and cellular response to DPAsV in primary mouse hepatocytes. Exposure of the hepatocytes to DPAsV resulted in cell damage accompanied by cellular accumulation of DPAsV in a time-dependent manner. The cell death caused by DPAsV was attributable to apoptosis. DPAsV activated a basic leucine-zipper transcription factor Nrf2 as determined by the nuclear translocation of Nrf2, anti-oxidant response element (ARE)-dependent luciferase activity, and upregulation of downstream gene products. However, gamma-glutamylcysteine synthetase heavy subunit chain (gamma-GCS(H)), which is regulated by Nrf2, underwent cleavage by activated caspase-3 to a 17 kDa fragment, leading to a minimal level of constitutive gamma-GCS(H) expression 72 h following the exposure (25 microM). Experiments with cycloheximide revealed that the DPAsV-mediated reduction in gamma-GCS(H) was due to a post-translational modification. The results suggest that DPAsV causes caspase-3-dependent cleavage of gamma-GCS(H) regardless of Nrf2 activation in primary mouse hepatocytes.
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PMID:Activation of the Nrf2 pathway, but decreased gamma-glutamylcysteine synthetase heavy subunit chain levels and caspase-3-dependent apoptosis during exposure of primary mouse hepatocytes to diphenylarsinic acid. 1762 25

In this study, we investigated the mechanisms of kahweol protection of neuronal cells from cell death induced by the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA). Pretreatment of SH-SY5Y cells with kahweol significantly reduced 6-OHDA-induced generation of ROS, caspase-3 activation, and subsequent cell death. Kahweol also up-regulated heme oxygenase-1 (HO-1) expression, which conferred neuroprotection against 6-OHDA-induced oxidative injury. Moreover, kahweol induced PI3K and p38 activation, which are involved in the induction of Nrf2, HO-1 expression, and neuroprotection. These results suggest that regulation of the anti-oxidant enzyme HO-1 via the PI3K and p38/Nrf2 signaling pathways controls the intracellular levels of ROS.
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PMID:The coffee diterpene kahweol induces heme oxygenase-1 via the PI3K and p38/Nrf2 pathway to protect human dopaminergic neurons from 6-hydroxydopamine-derived oxidative stress. 1859 83

In the present work, we investigated the protective effects of the ethanol extract of Aralia continentalis roots (AC) on tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in a cultured Hepa1c1c7 cell line and in mouse liver. Pretreatment with AC prior to the administration of t-BHP significantly prevented the increase in serum levels of hepatic enzyme markers (ALT, AST) and lipid peroxidation and reduced oxidative stress, as measured by glutathione content, in the liver. Histopathological evaluation of the livers also revealed that AC reduced the incidence of liver lesions. The in vitro study showed that AC significantly reduced t-BHP-induced oxidative injury in Hepa1c1c7 cells, as determined by cell cytotoxicity, intracellular glutathione content, lipid peroxidation, reactive oxygen species (ROS) levels, and caspase-3 activation. Also, AC up-regulated phase II genes including heme oxygenase-1 (HO-1), NAD(P)H:quinone reductase, and glutathione S-transferase. Moreover, AC induced Nrf2 nuclear translocation and ERK1/2 and p38 activation, pathways that are involved in inducing Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of AC against t-BHP-induced hepatotoxicity may, at least in part, be due to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the ERK1/2 and p38/Nrf2 signaling pathways.
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PMID:Protective mechanisms of Aralia continentalis extract against tert-butyl hydroperoxide-induced hepatotoxicity: in vivo and in vitro studies. 1882 57

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. The phytoestrogen puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicines for thousands of years. Recent studies have indicated that the estrogen receptor (ER), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, non-nuclear function of ER that may be relevant in cytoprotection. In this study, we demonstrate that the phytoestrogen puerarin inhibits tert-butyl hydroperoxide (t-BHP)-induced oxidative injury via an ER-dependent Gbeta1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of Hepa1c1c7 and HepG2 cells with puerarin significantly reduced t-BHP-induced caspase-3 activation and subsequent cell death. Also, puerarin up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, puerarin induced Nrf2 nuclear translocation, which is upstream of puerarin-induced HO-1 expression, and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Puerarin-induced up-regulation of HO-1 and cytoprotection against t-BHP were abolished by silencing Nrf2 expression with specific siRNA. Also, puerarin-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that puerarin augments cellular antioxidant defense capacity through ER-dependent HO-1 induction via the Gbeta1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress.
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PMID:Mechanism of phytoestrogen puerarin-mediated cytoprotection following oxidative injury: estrogen receptor-dependent up-regulation of PI3K/Akt and HO-1. 1884 76

Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this study, we found that arsenite (As(3+)) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53(+/+) and p53(-/-) mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53(-/-) cells than in the p53(+/+) cells. To examine this difference further, a systems-based genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As(3+). A significant alteration in the Nrf2-mediated oxidative stress response pathway was found in both genotypes. In p53(+/+) MEFs, As(3+) induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53(-/-) MEFs, As(3+) induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that As-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53-dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent.
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PMID:Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways. 1892 88

As with Usher syndrome observed in humans, the two main phenotypes of the tubby mouse are progressive hearing loss and retinal degeneration. Yet, the mechanism underlying the tub-related cochlear degeneration is still unclear. The reduction/oxidation (redox) imbalance in the cell is related to many kinds of diseases. This study examined expressions of thioredoxin (Trx) and Trx reductase (TrxR), an important redox system in the cell, and the related upstream and downstream proteins of the Trx/TrxR in the tubby mouse cochlea. This report also examined the therapeutic effect of sulforaphane (SF) on the cochlear degeneration, which showed a protective effect on the tub-related retinal degeneration in our previous report. The results showed that the tub-mutation resulted in a significant suppression of Trx and TrxR expressions. Expression level of Nrf2 (NFE2 related factor 2), a transcription factor that regulates expression of Trx and TrxR and others, was also suppressed in the tubby mouse cochlea. Furthermore, a lowered level of activated extracellular signal-regulated kinase (p-ERK) was observed in the tubby mouse cochlea. In contrast, caspase-3 expression and activity were enhanced in the tubby mouse, suggesting apoptotic cell death. The tub-related molecular alterations in the cochlea were prevented by chronic treatment with SF. As a result, the SF-treatment significantly delayed the tub-related cochlear degeneration. Other unknown proteins may contribute to tubby-related degeneration because Nrf2 regulates many other antioxidants besides Trx/TrxR and sulforaphane did not prevent cochlear degeneration completely although it completely prevented alterations of Nrf2 and Trx/TrxR.
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PMID:Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane. 1911 66

Coordinated regulation of PI3-kinase (PI3K) and the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) plays a pivotal role in various cell functions. PTEN is deficient in many cancer cells, including Jurkat human leukemia. Here, we demonstrate that the status of PTEN determines cellular susceptibility to oxidative stress through antioxidant-responsive element (ARE)-mediated transcription of detoxification genes. We found that ferritin H transcription was robustly induced in tert-butylhydroquinone (t-BHQ)-treated Jurkat cells via an ARE, and it was due to PTEN deficiency. Chromatin immunoprecipitation assays revealed that p300/CREB-binding protein (CBP) histone acetyltransferases and Nrf2 recruitment to the ARE and Bach1 release were blocked by the PI3K inhibitor LY294002, along with the partial inhibition of Nrf2 nuclear accumulation. Furthermore, acetylations of histone H3 Lys9 and Lys18, and deacetylation of Lys14 were associated with the PI3K-dependent ARE activation. Consistently, PTEN restoration in Jurkat cells inhibited t-BHQ-mediated expression of ferritin H and another ARE-regulated gene NAD(P)H:quinone oxidoreductase 1. Conversely, PTEN knockdown in K562 cells enhanced the response to t-BHQ. The PTEN status under t-BHQ treatment affected hydrogen peroxide-mediated caspase-3 cleavage. The PI3K-dependent ferritin H induction was observed by treatment with other ARE-activating agents ethoxyquin and hemin. Collectively, the status of PTEN determines chromatin modifications leading to ARE activation.
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PMID:Role of the tumor suppressor PTEN in antioxidant responsive element-mediated transcription and associated histone modifications. 1915 75


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