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)

The evolution of brain injury was examined in mice subjected to focal cerebral ischemia as induced by 30 min of intraluminar thread occlusion of the middle cerebral artery, followed by 3 h to 3 days of reperfusion. Metabolic dysfunctions were studied by 3H-leucine autoradiography for the measurement of cerebral protein synthesis and by regional ATP bioluminescent imaging. Metabolic changes were compared with responses of the genes c-fos, c-jun, heat-shock protein gene (hsp)72, p53-activated gene (pag)608 and caspase-3, which were investigated by in situ hybridization histochemistry and immunocytochemistry, and correlated with the degree of DNA fragmentation, as assessed by the terminal TdT-mediated dUTP-biotin nick end labeling method. Intraluminar thread occlusion led to a reproducible reduction of cerebral laser Doppler flow to 20-30% of control. Thread withdrawal was followed by a short-lasting post-ischemic hyperperfusion to approximately 120%. In non-ischemic control animals, fractional protein synthesis values of 0.81+/-0.26 and 0.94+/-0.23 were obtained. Thread occlusion resulted in a suppression of protein synthesis throughout the territory of the middle cerebral artery after 3 h of reperfusion (0.04+/-0.08 in caudate-putamen and 0.14+/-0.19 in somatosensory cortex, P<0.05). Protein synthesis partly recovered in the cortex after 24 h and 3 days (0.71+/-0.40 and 0.63+/-0.26, respectively), but remained suppressed in the caudate-putamen (0.14+/-0.22 and 0.28+/-0.28). Regional ATP levels did not show any major disturbances at the reperfusion times examined. Thread occlusion resulted in a transient increase of c-fos mRNA levels in ischemic and non-ischemic parts of the cortex and caudate-putamen at 3 h after ischemia, which suggests that spreading depressions were elicited in the tissue. At the same time, c-jun and hsp72 mRNAs were elevated only in ischemic brain areas showing inhibition of protein synthesis. C-fos and c-jun responses completely disappeared within 24 h of reperfusion. Hsp72 mRNA levels remained elevated in the cortex after 24 h, but decreased to basal values in the caudate-putamen. Twenty-four hours after reperfusion, pag608 and caspase-3 mRNA levels increased in the caudate-putamen, where protein synthesis rates were still reduced, and remained elevated even after 3 days. However, pag608 and caspase-3 mRNA levels did not increase in the cortex, where protein synthesis recovered. After 24 h and 3 days, functionally active p20 fragment of caspase-3 was detected in the caudate-putamen, closely associated with the appearance of DNA fragmented cells. Neither activated caspase-3 nor DNA fragmentation were noticed in the cortex.In summary, the suppression of protein synthesis is reversible in the ischemia-resistant cortex following 30 min of thread occlusion in mice, but persists in the vulnerable caudate-putamen. In the caudate-putamen, apoptotic programs are induced, closely in parallel with the manifestation of delayed cell death. Thus, the recovery of protein synthesis may be a major factor influencing tissue survival after transient focal ischemia.
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PMID:Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. 1145 82

This study was designed to examine the influence of zinc depletion and supplementation on the expression of p53 gene, target genes of p53, and caspase-3 activity in normal human bronchial epithelial (NHBE) cells. A serum-free, low-zinc medium containing 0.4 micromol/l of zinc [zinc deficient (ZD)] was used to deplete cellular zinc over one passage. In addition, cells were cultured for one passage in media containing 4.0 micromol/l of zinc [zinc normal (ZN)], which represents normal culture concentrations (Clonetics); 16 micromol/l of zinc [zinc adequate (ZA)], which represents normal human plasma zinc levels; or 32 micromol/l of zinc [zinc supplemented (ZS)], which represents the high end of plasma zinc levels attainable by oral supplementation in humans. Compared with ZN cells, cellular zinc levels were 76% lower in ZD cells but 3.5-fold and 6-fold higher in ZA and ZS cells, respectively. Abundances of p53 mRNA and nuclear p53 protein were elevated in treatment groups compared with controls (ZN). For p53 mRNA abundance, the highest increase (3-fold) was observed in ZD cells. In contrast, the highest increase (17-fold) in p53 nuclear protein levels was detected in ZS cells. Moreover, gadd45 mRNA abundance was moderately elevated in ZD and ZA cells and was not altered in ZS cells compared with ZN cells. Furthermore, the only alteration in c-fos mRNA and caspase-3 activity was the twofold increase and the 25% reduction, respectively, detected in ZS compared with ZN cells. Thus p53, gadd45, and c-fos and caspase-3 activity appeared to be modulated by cellular zinc status in NHBE cells.
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PMID:Zinc status affects p53, gadd45, and c-fos expression and caspase-3 activity in human bronchial epithelial cells. 1150 52

Upregulation of calpain, a Ca(2+)-activated cysteine protease, has been implicated in apoptosis and tissue degeneration in spinal cord injury (SCI) that over time spreads from the site of injury to the surrounding regions. We examined calpain content and activity, regulation of immediate early genes (IEGs) such as c-jun and c-fos, reactive astrogliosis as the expression of glial fibrillary acidic protein (GFAP), and apoptosis-related features such as caspase-3 mRNA expression and internucleosomal DNA fragmentation in 1-cm long spinal cord segments (S1, distant rostral; S2, adjacent rostral; S3, lesion or injury; S4, adjacent caudal; and S5, distant caudal) following SCI in rats. Calpain content and production of 150 kD calpain-cleaved alpha-fodrin fragment, expression of IEGs, reactive astrogliosis, and apoptotic features were highly increased in the lesion (S3), moderately in adjacent areas (S2 and S4), and slightly in distant areas (S1 and S5) in SCI rats when compared to sham animals. Administration of the calpain-specific inhibitor E-64-d (1 mg/kg) to SCI rats continuously for 24 h inhibited calpain activity and other factors contributing to apoptosis in the lesion and surrounding areas, indicating that calpain played a key role in the pathophysiology of SCI. The results obtained from this animal model of SCI suggest that calpain inhibitor can provide neuroprotection in patients with SCI.
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PMID:Inhibition of calpain-mediated apoptosis by E-64 d-reduced immediate early gene (IEG) expression and reactive astrogliosis in the lesion and penumbra following spinal cord injury in rats. 1159 98

The neurotoxic damage caused by methamphetamine (METH) is characterized by nerve terminal destruction and/or degeneration of the dopaminergic and serotonergic systems in striatum and hippocampus. It has been hypothesized that intraneural dopamine (DA) redistribution from synaptic vesicles to cytoplasmic compartments produced by METH is an important factor for its neurotoxicity. The METH-induced redistribution of DA is thought to occur after an increased production of DA-based reactive oxygen species (ROS) (e.g., oxygen radicals and hydroxyl radicals) by auto-oxidation or enzymatic degradation, and METH-induced ROS produces an oxidative stress and depletion of energy stores. Furthermore, the glutamatergic system and nitric oxide (NO) may also contribute to METH-induced neurotoxicity. Recently, studies using several knockout strains of mice lacking the DA transporter, the monoamine vesicle transporter-2, c-fos, or neuronal NO synthase confirm a possible role of these factors in METH-induced neurotoxicity. Moreover, it has been proposed that METH causes the apoptosis and activation of cell-death-related genes. For example, METH-induced neurotoxicity is reduced in bcl-2-over expressing neural cell and p53 knockout mice and also induces the activation of caspase 3. Therefore in this review, we discuss the relationship between ROS formation, oxidative stress, and apoptosis in METH-induced neurotoxicity.
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PMID:[A recent trend in methamphetamine-induced neurotoxicity]. 1205 Aug 51

The exposure of mammalian cells to UV irradiation induces the expression of immediate early genes such as c-jun and c-fos and activates the transcription factors AP-1 and NF-kappaB. JunD is one of the three members of the Jun family and shares some functional characteristics with c-Jun. In the present study, we found that the exposure of myeloblastic leukemia ML-1 cells to UV light (UVC) caused a significant increase in junD mRNA expression within 5 min that persisted for a period of 3 h. The activation of protein kinase C (PKC) with 12-O-tetradecaoylphorbol-13-acetate (TPA) also induced increases in junD expression similar to those of UV irradiation. In addition, UV irradiation- and TPA-induced increases in junD expression were completely abolished by GF-109203X, a PKC-specific inhibitor. UV irradiation activated intracellular signaling pathways including extracellular regulated kinase-2 (Erk-2), c-Jun N-terminal kinases-1 (JNK-1), and p38. However, TPA-induced activation of PKC affected only Erk-2 activity, and GF-109203X (a PKC inhibitor) markedly suppressed UV-induced Erk-2 activation. To further investigate the effect of UV-induced Erk-2 activation on the expression of junD mRNA, cDNA encoding mitogen-activated protein kinase kinase (MEK1) was overexpressed in ML-1 cells. The overexpression of MEK1 enhanced substantially junD expression in response to UV or TPA. In contrast, the suppression of Erk activation with PD98059, a specific inhibitor of MEK1, inhibited UV- and TPA-induced junD mRNA expression, UV-induced increases in caspase-3 activities, and cell death. In addition, the overexpression of junD enhanced the UV irradiation-induced increases in caspase-3 activity and cell death. We conclude that UV irradiation-induced increases in junD expression in ML-1 cells are mediated through activation of the PKC-coupled Erk-2 signaling pathway and play an important role in ML-1 cell apoptosis.
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PMID:Ultraviolet-induced junD activation and apoptosis in myeloblastic leukemia ML-1 cells. 1208 1

We have demonstrated that Ad.betaGal, a broadly used adenoviral vector of serotype 5, binds and induces proto-oncogene c-fos expression in quiescent cultures of mouse brain astrocytes. As observed in Northern blots, the expression of this immediate early gene is induced by viral infection in a dose-dependent manner, peaking at a multiplicity of infection (m.o.i.) of 100. The expression of c-fos is transient, being maximal after 30 min and disappearing 2 h after infection. A previously reported method was used to study the presence of receptors for adenovirus in the cellular membrane of murine astrocytes. After absorption of the virus, rabbit antibodies and 125I-protein A were used to form a sandwich on the cellular surface, and 9000 adenovirus-specific receptors were demonstrated on each astrocytic cell. Binding was temperature dependent and reached a plateau after 60 min. The specificity of c-fos induction is demonstrated by its neutralization by anti-adenovirus-specific antibodies. Although clear apoptosis cannot be demonstrated in vitro by DNA laddering, maybe due to a lack of sensitivity of the method, a statistically significant increase in caspase-3 activity is demonstrated in astrocyte cultures infected at a m.o.i. of 100 by adenovirus. Furthermore, a perfect colocalization is shown in vivo between cells infected with the Ad.betaGal vector and apoptotic astrocytes, as demonstrated by TdT-mediated dUTP nick end labeling (TUNEL) staining. The purpose of our study was to ascertain the potential for adenovirus as a gene therapy vector for neural disorders caused by astrocyte dysfunctions.
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PMID:Binding of adenovirus to its receptors in mouse astrocytes induces c-fos proto-oncogene and apoptosis. 1208 20

Chronic treatment with calcium ionophore A23187 in NGF-differentiated cells results in cell death that is time- and concentration-dependent. Additionally, PC12 cells codifferentiated with NGF and dBcAMP become dependent on these factors for survival and undergo apoptosis when both factors are withdrawn. We show that in both cases there is a prolonged induction of c-Fos which correlates with cell death. Its continual activation in PC12 cells overexpressing c-FosER results in caspase-3 cleavage and rapid cell death. Specific phosphorylation of CREB/CREM(tau) transactivators or their binding to CRE of c-fos was observed. Our results indicate that prolonged c-Fos induction activates p53. There is increased nuclear localization of p53, p21 and Bax levels are induced in NGF/dBcAMP-deprived c-FosER cells, and dominant negative p53 inhibits cell death induced either by serum deprivation or by c-Fos. Overall these data implicate AP-1 as a nuclear target of signal transduction pathways which plays a role in the activation of apoptosis.
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PMID:Molecular mechanisms of neuronal cell death: implications for nuclear factors responding to cAMP and phorbol esters. 1235 47

The aim of the present study was to establish whether aniracetam is capable of protecting cultured rat astrocytes against ischemic injury. Treatment of the cultures with aniracetam (1, 10 and 100 mM) during 24 h ischemia simulated in vitro significantly decreased the number of apoptotic cells. The antiapoptotic effects of the drug were confirmed by the increase of intracellular ATP and phosphocreatine (PCr) levels and the inhibition of the caspase-3 activity. Aniracetam also attenuated cellular oxidative stress by decreased production of reactive oxygen species (ROS). These effects were associated with the decrease in levels of c-fos and c-jun mRNA in primary astrocyte cultures exposed to 24 h ischemia. When cultured astrocytes were incubated during 24 h simulated ischemia with wortmannin, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor or PD98059, a mitogen-activated protein (MAP)/extracellular signal regulated kinase (ERK) (MEK) inhibitor the cell apoptosis was accelerated. This effect was antagonized by adding 100 mM aniracetam to the culture medium. These findings suggest that the protective effect of aniracetam is mediated by PI 3-kinase and MEK pathways in the downstream mechanisms.
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PMID:Aniracetam attenuates apoptosis of astrocytes subjected to simulated ischemia in vitro. 1238 65

Shiga toxins made by Shiga toxin-producing Escherichia coli (STEC) are associated with hemolytic uremic syndrome. Shiga toxins (Stxs) may access the host systemic circulation by absorption across the intestinal epithelium. The effects of Stxs on this cell layer are not completely understood, although animal models of STEC infection suggest that, in the gut, Stxs may participate in both immune activation and apoptosis. Stxs have one enzymatically active A subunit associated with five identical B subunits. The A subunit inactivates ribosomes by cleaving a specific adenine from the 28S rRNA. We have previously shown that Stxs can induce multiple C-X-C chemokines in intestinal epithelial cells in vitro, including interleukin-8 (IL-8), and that Stx-induced IL-8 expression is linked to induction of c-Jun mRNA and p38 mitogen-activated protein (MAP) kinase pathway activity. We now report Stx1 induction of both primary response genes c-jun and c-fos and activation of the stress-activated protein kinases, JNK/SAPK and p38, in the intestinal epithelial cell line HCT-8. By 1 h of exposure to Stx1, mRNAs for c-jun and c-fos are induced, and both JNK and p38 are activated; activation of both kinases persisted up to 24 h. Stx1 enzymatic activity was required for kinase activation; a catalytically defective mutant toxin did not activate either. Stx1 treatment of HCT-8 cells resulted in cell death that was associated with caspase 3 cleavage and internucleosomal DNA fragmentation; this cytotoxicity also required Stx1 enzymatic activity. Blocking Stx1-induced p38 and JNK activation with the inhibitor SB202190 prevented cell death and diminished Stx1-associated caspase 3 cleavage. In summary, these data link the Stx1-induced ribotoxic stress response with both chemokine expression and apoptosis in the intestinal epithelial cell line HCT-8 and suggest that blocking host cell MAP kinases may prevent these Stx-associated events.
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PMID:Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. 1259 68

To investigate apoptosis induced by selenite in hepatocytes in vivo, rats received a single injection of sodium selenite immediately after partial hepatectomy. Characteristic DNA fragmentation in gel electrophoresis and in situ end-labeling and the increase in caspase-3 activity were observed at 4 h after partial hepatectomy with selenite injection. The activation of Jun N-terminal kinase (JNK) was observed as early as 15 min and increased to about 10-fold the maximal level of the control at 1 and 2 h after partial hepatectomy in selenite-injected rats, while a transient increase was observed at 1 h in the control. Western blot analysis revealed that the c-Jun and the phosphorylated c-Jun protein markedly increased after 30 min and reached a maximal level at 1 and 2 h after partial hepatectomy with selenite injection, although c-Jun and a faint band of the phosphorylated c-Jun were observed after 1 h in the control. The levels of c-jun mRNA and c-Fos protein and mRNA in selenite-injected rats also increased more than in the control. The rise in the p53 protein level after partial hepatectomy with selenite injection was followed by the upregulation of p21(WAF1/CIP1) mRNA and protein expression. These results suggested that selenite induced apoptosis accompanied by the activation of caspase-3 and JNK and the upregulation of c-jun, c-fos, p53 and p21(WAF1/CIP1) at the early stage of liver regeneration.
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PMID:Jun N-terminal kinase activation and upregulation of p53 and p21(WAF1/CIP1) in selenite-induced apoptosis of regenerating liver. 1280 46


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