Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of transforming growth factor-beta type 1- (TGFbeta1) mediated signaling occurs in response to cell injury affecting stem-type cells and hepatocytes in liver. In this work we used WB stemlike liver epithelial cells and p53-defective CWSV-1 nontumorigenic rat hepatocytes to investigate the possible roles of caspases and oxidative stress in TGFbeta1 signaling. TGFbeta1 significantly increased the level of 4-hydroxy-2-nonenal (4-HNE), a stable product of lipid peroxidation. In addition, TGFbeta1-treated cells exhibited activation of caspases that accompanied by enhanced cleavage of the caspase substrate poly(ADP)-ribose polymerase (PARP) and induction of apoptosis. WB cells were twice as sensitive as sensitive as CWSV-1 cells to induction of TGFbeta1 apoptosis. TGFbeta1-apoptosis was significantly reduced when cells were treated with TGFbeta1 in the presence of inhibitors of caspase-1, -3, -8, and -9. Importantly, in addition to suppression of apoptosis, treatment of cells with the caspase-3 inhibitor Z-DEVD-FMK in the presence of TGFbeta1 suppressed the formation 4-HNE and restored mitotic activity. Together, these data suggest TGFbeta1 induces activation of a caspase signaling cascade that includes an oxidative damage response, PARP cleavage, and apoptosis that do not require intact p53 in rat hepatocytes.
Exp Mol Pathol 2003 Jun
PMID:Activation of a caspase-dependent oxidative damage response mediates TGFbeta1 apoptosis in rat hepatocytes. 1278 12

Objective. - Mice with targeted deletion of caspase-1 (interleukin-1beta (IL-1beta)-converting enzyme) lack the active forms of IL-1beta and IL-18, two cytokines implicated in maladaptive ventricular remodeling following cardiac injury. We, therefore, investigated the extent of ventricular dilation in caspase-1-knockout (KO) mice. Methods and results. - Transthoracic echocardiography was performed at days 1, 4, and 9 following left anterior descending artery ligation in caspase-1-KO and wild-type (WT) control animals, including M-mode and short-axis imaging at both mid-papillary and apical levels. Although initial post-operative mortality was lower in KO than in WT animals (21.4% WT, 12.0% KO, P < 0.001), there was no difference in mortality between 24 h and 9 d (P = n.s.). Caspase-1 KOs exhibited significantly less mid-papillary ventricular dilatation at days 4 and 9 compared to day 1 post-myocardial infarction (MI) (P < 0.05). Caspase-1 KOs also had a marked (50%) reduction in the level of matrix metalloproteinase 3 (MMP-3), although no significant changes occurred in other MMPs or in tissue inhibitors of metalloproteinase 1 levels by immunoblot analysis. Although IL-beta plasma levels were not detectable, both IL-18 levels and the rate of apoptosis in remodeling, non-infarcted muscle were significantly higher in WT compared to caspase-1-KO animals.Conclusion. - Mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, possibly due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis after experimental MI.
J Mol Cell Cardiol 2003 Jun
PMID:Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. 1278 86

Caspase-11 is an inducible protease that plays an important role in both inflammation and apoptosis. Inflammatory stimuli induce and activate caspase-11, which is required for the activation of caspase-1 or interleukin-1beta (IL-1beta) converting enzyme (ICE). Caspase-1 in turn mediates the maturation of proinflammatory cytokines such as IL-1beta, which is one of the crucial mediators of neurodegeneration in the central nervous system. Here, we report that hypoxic exposure of cultured brain microglia (BV-2 mouse microglia cells and rat primary microglial cultures) induces expression and activation of caspase-11, which is accompanied by activation of caspase-1 and secretion of mature IL-1beta and IL-18. Hypoxic induction of caspase-11 was observed in both mRNA and protein levels, and was mediated through p38 mitogen-activated protein kinase pathway. Transient global ischemia in rats also induced caspase-11 expression and IL-1beta production in hippocampus supporting our in vitro findings. Caspase-11-expressing cells in hippocampus were morphologically identified as microglia. Taken together, our results indicate that hypoxia induces a sequential event-caspase-11 induction, caspase-1 activation, and IL-1beta release-in brain microglia, and point out the importance of initial caspase-11 induction in hypoxia-induced inflammatory activation of microglia.
Brain Res Mol Brain Res 2003 Jun 10
PMID:Hypoxic induction of caspase-11/caspase-1/interleukin-1beta in brain microglia. 1282 20

A developmental model of spinal cord injury in the embryonic chick was specifically developed to characterize the involvement of caspases in injury-induced oligodendrocyte apoptosis remote from the lesion and the ability of caspase inhibitors to attenuate this process. Developmental apoptosis in the cervical spinal cord increased within the white matter between embryonic days 13 and 18, the period of myelination of this region. Spinal cord transection during this period induced a rapid increase in apoptotic cells in the ventral and lateral white matter over several millimeters caudal to the injury. Immunostaining identified large numbers of these cells as oligodendrocytes. Catalytic activity assays and immunostaining demonstrated caspase-3-like but not caspase-1-like activity to be involved in this apoptotic response. In vivo application of specific caspase inhibitors significantly attenuated transection-induced apoptosis. Thus, we describe a developmental period during which spinal oligodendrocytes exhibited a heightened, caspase-dependent sensitivity to transection-induced apoptosis that is attenuated by caspase inhibition.
Mol Cell Neurosci 2003 Jul
PMID:Caspase inhibition attenuates transection-induced oligodendrocyte apoptosis in the developing chick spinal cord. 1283 23

Interleukin-1 (IL-1) has been implicated in neuroimmune responses and has pleiotropic actions in the brain. Compelling evidence has shown that IL-1 is a major mediator of inflammation and the progression of cell death in response to brain injury and cerebral ischemia. Its expression is strongly increased in these pathological conditions, and central administration of exogenous IL-1 significantly exacerbates ischemic brain damage. In contrast, inhibiting IL-1 actions (by intracerebroventricular [icv] injection of IL-1ra, neutralizing antibody to IL-1 or caspase-1 inhibitor) significantly reduces ischemic brain damage. IL-1 acts by binding to the IL-1 type-I receptor (IL-1RI), which is to date, the only known functional receptor for IL-1. However, our recent investigations suggest that IL-1 can act independently of IL-1RI, raising the possibility that additional, as yet undiscovered, receptor(s) for IL-1 exist in the brain. The recent characterization of putative, new IL-1 ligands and new IL-1 receptor-related molecules leads to the hypothesis that there might be alternative IL-1 signaling pathway(s) in the central nervous system (CNS).
Mol Neurobiol 2003 Jun
PMID:The expanding interleukin-1 family and its receptors: do alternative IL-1 receptor/signaling pathways exist in the brain? 1284 50

Inhibition of IL-1beta convertase has been shown to decrease inflammation and apoptosis, which are features of the neointimal development after vascular interventions. The aim of our study was to reduce neointimal proliferation after stenting of the porcine coronary artery, using the irreversible IL-1beta convertase and caspase-1 inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloromethyl-ketone (Ac-YVAD-cmk). Before coronary stent implantation, 8 pigs received an intracoronary infusion of 50 mg Ac-YVAD-cmk into the left coronary artery (group 1, n = 8), while 8 animals served as untreated controls (group 2). After 4 weeks, coronary angiography and intracoronary ultrasound (IVUS) with 3D measurements were performed. IVUS revealed a smaller in-stent intimal volume (27.3 +/- 11.6 vs. 75.8 +/- 18.4 mm3, p < 0.005) and a decreased maximal percentage area stenosis (36.1 +/- 8.5 vs. 69.0 +/- 8.2%, p < 0.001) in group 1 vs. group 2. A smaller maximal neointimal thickness (0.63 +/- 0.28 vs. 1.75 +/- 0.94 mm, p < 0.005) and a decreased maximal neointimal area (2.14 +/- 1.29 vs. 5.03 +/- 1.92 mm2, p < 0.005), assessed by computerized planimetry, were found in group 1 vs. group 2. Lower apoptotic indices of the neointimal cells were observed in the treated animals (3.0 vs. 13.4% of total intimal cells, p < 0.05). The coronary arterial tissue IL-1beta level was significantly decreased in the animals treated with Ac-YVAD-cmk (0.254 +/- 0.162 vs. 0.463 +/- 0.307 pg/mg protein, p < 0.05), and exhibited a positive linear correlation (r = 0.581, p = 0.013) with the in-stent plaque volume. In conclusion, intracoronary administration of Ac-YVAD-cmk before coronary artery stenting results in significantly decreased neointimal hyperplasia due to the inhibition of local IL-1beta production and decreased neointimal apoptosis.
Mol Cell Biochem 2003 Jul
PMID:Inhibition of interleukin-1beta convertase is associated with decrease of neointimal hyperplasia after coronary artery stenting in pigs. 1295 96

Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in eukaryotic cells and has been implicated in cell dysfunction in reperfusion injury. In this study we investigated the role of PARP-1 on apoptosis in early myocardial reperfusion injury. Mice genetically deficient of PARP-1 (PARP-1-/-) and wild-type littermates were subjected to myocardial ischemia and reperfusion. Myocardial injury was assessed by measuring the serum levels of creatine phosphokinase and oligonucleosomal DNA fragments in the infarcted area. Expression of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax, was analyzed by Western blot. Activation of caspases, important executioners of apoptosis, and activation of the nuclear factor kappa B (NF-kappa B) pathway were evaluated. Gene expression profiles for apoptotic regulators between PARP-1-/- and wild-type mice also were compared. Myocardial damage in PARP-1-/- mice was reduced significantly, as indicated by lower serum creatine phosphokinase levels and reduction of apoptosis, as compared with wild-type mice. Western blot analyses showed increased expression of Bcl-2, which was associated with reduction of caspase-1 and caspase-3 activation. This cardioprotection was associated with significant reduction of the activation of I kappa B kinase complex and NF-kappa B DNA binding. Microarray analysis demonstrated that the expression of 29 known genes of apoptotic regulators was significantly altered in PARP-1-/- mice compared with wild-type mice, whereas 6 known genes were similarly expressed in both genotypes. The data indicate that during reperfusion absence of PARP-1 leads to reduction of myocardial apoptosis, which is associated with reduced NF-kappa B activation and altered gene expression profiles.
Mol Med
PMID:Absence of poly(ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. 1457 22

Diversification of bacterial species and pathotypes is largely caused by horizontal transfer of diverse DNA elements such as plasmids, phages and genomic islands (e.g. pathogenicity islands, PAIs). A PAI called high-pathogenicity island (HPI) carrying genes involved in siderophore-mediated iron acquisition (yersiniabactin system) has previously been identified in Yersinia pestis, Y. pseudotuberculosis and Y. enterocolitica IB strains, and has been characterized as an essential virulence factor in these species. Strikingly, an orthologous HPI is a widely distributed virulence determinant among Escherichia coli and other Enterobacteriaceae which cause extraintestinal infections. Here we report on the HPI of E. coli strain ECOR31 which is distinct from all other HPIs described to date because the ECOR31 HPI comprises an additional 35 kb fragment at the right border compared to the HPI of other E. coli and Yersinia species. This part encodes for both a functional mating pair formation system and a DNA-processing region related to plasmid CloDF13 of Enterobacter cloacae. Upon induction of the P4-like integrase, the entire HPI of ECOR31 is precisely excised and circularised. The HPI of ECOR31 presented here resembles integrative and conjugative elements termed ICE. It may represent the progenitor of the HPI found in Y. pestis and E. coli, revealing a missing link in the horizontal transfer of an element that contributes to microbial pathogenicity upon acquisition.
Mol Microbiol 2004 Feb
PMID:A novel integrative and conjugative element (ICE) of Escherichia coli: the putative progenitor of the Yersinia high-pathogenicity island. 1473 Dec 83

Irofulven (hydroxymethylacylfulvene) is a novel antitumor drug, which acts by alkylating cellular macromolecular targets. The drug is a potent inducer of apoptosis in various types of tumor cells, whereas it is nonapoptotic in normal cells. This study defined molecular responses to irofulven involving mitochondrial dysfunction and leading to death of prostate tumor LNCaP-Pro5 cells. Irofulven caused early (2-5 hours) translocation of the proapoptotic Bax from cytosol to mitochondria followed by the dissipation of mitochondrial membrane potential and cytochrome c release at 4 to 12 hours. These effects preceded caspase activation and during the first 6 hours were not affected by caspase inhibitors. Processing of caspase-9 initiated the caspase cascade at approximately 6 hours and progressed over time. The activation of the caspase cascade provided a positive feedback loop that enhanced Bcl-2-independent translocation and cytochrome c release. General and specific caspase inhibitors abrogated irofulven-induced apoptotic DNA fragmentation with the following order of potency: pan-caspase > or = caspase-9 > caspase-8/6 > caspase-2 > caspase-3/7 > caspase-1/4. Abrogation of caspase-mediated DNA fragmentation failed to salvage irofulven-treated cells from growth inhibition and loss of viability, demonstrating a substantial contribution of a caspase-independent cell death. Monobromobimane, an inhibitor of alternative caspase-independent apoptotic pathway that is mediated by mitochondrial permeability transition, antagonized both apoptosis, measured as phosphatidylserine externalization, and cytotoxicity of irofulven. Collectively, the results indicate that irofulven-induced signaling is integrated at the level of mitochondrial dysfunction. The induction of both caspase-dependent and caspase-independent death pathways is consistent with pleiotropic effects of irofulven, which include targeting of cellular DNA and proteins.
Mol Cancer Ther 2004 Nov
PMID:Caspase-mediated apoptosis and caspase-independent cell death induced by irofulven in prostate cancer cells. 1554 77

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.
Mol Psychiatry 2005 Apr
PMID:Support for involvement of neuregulin 1 in schizophrenia pathophysiology. 1554 78


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