Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed ischemic death of neurones is observed selectively in CA1 region of hippocampus at 3-4 days of reperfusion. Signals generated immediately during and after ischemia are further propagated by a variety of kinases, proteases and phosphatases. Tissue samples from dorsal (vulnerable) and abdominal (resistant) parts of gerbil hippocampi were collected to determine the activation state of key signaling molecules: Akt, Raf-1, JNK, ERK1/2 in the course of reperfusion after 5 min of global cerebral ischemia. Western blot analysis of phosphorylated forms of the kinases revealed persistent activation of JNK, being limited mostly to vulnerable CA1 region. On the contrary, activation of ERK, although observed transiently in both parts, was enhanced for a longer time in the abdominal hippocampus. The levels of the active/phosphorylated Akt and Raf-1 kinases did not change significantly during the recovery period. No significant correlation between postischemic JNK activation and c-Jun phosphorylation or its contribution to AP1-like complex formation was found. In contrast, the amount of active JNK linked with mitochondrial membranes was significantly increased and preceded neuronal death in CA1. In the same period of time the AP1 complex, augmented in CA1 region, did not appear to contain a classical c-Fos protein. These results are consistent with the theory that either long-lasting activation of JNK and/or contrasting ERK and JNK activities in critical time of reperfusion, contribute to selective apoptosis of CA1 neurons. This, in connection with the translocation of activated JNK to mitochondria and time/regional differences in AP1 binding protein complexes can affect final postischemic outcome.
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PMID:Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria. 1259 Nov 60

1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. 2. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. 3. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 micro m in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation. 4. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. 6. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.
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PMID:A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats. 1259 18

The Bad signaling pathway contributes to the regulation of apoptosis after a variety of cell death stimuli, and Bad plays a key role in determining cell death or survival. We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduces apoptotic cell death after transient focal cerebral ischemia (tFCI). However, both the role of the Bad pathway after tFCI and the role of oxygen free radicals in the regulation of apoptosis remain unknown. To clarify these issues, we used an in vivo tFCI model of SOD1 transgenic mice and wild-type mice. Moreover, to examine the role of protein kinase A (PKA) in the Bad pathway after tFCI, we administered the PKA inhibitor, H89, into the mouse brain after tFCI. Immunohistochemistry and Western blot analysis showed that dephosphorylation and translocation of Bad were detected early after tFCI and that they were promoted by H89 treatment but prevented by SOD1. Coimmunoprecipitation revealed that the dimerization of Bad progressed with 14-3-3 (Bad/14-3-3) and with Bcl-x(L) (Bad/Bcl-x(L)) after tFCI. Moreover, Bad/14-3-3 was prevented by H89 treatment but promoted by SOD1. Bad/Bcl-x(L) was prevented by SOD1 but promoted by H89 treatment. A cell death assay revealed that apoptotic-related DNA fragmentation was aggravated by H89 treatment but reduced by SOD1. These results suggest that the Bad pathway mediated by PKA is involved in apoptotic cell death after tFCI and that overexpression of SOD1 may attenuate this apoptotic cell death.
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PMID:Overexpression of copper/zinc superoxide dismutase in transgenic mice protects against neuronal cell death after transient focal ischemia by blocking activation of the Bad cell death signaling pathway. 1262 75

Previous studies suggested that pro-apoptotic stimuli may trigger a fatal reactivation of cell cycle elements in postmitotic neurons. Supporting this hypothesis, small molecule inhibitors of cyclin-dependent kinases (CDKs), which are known primarily as cell cycle regulators, are neuroprotective. However, available CDK inhibitors cannot discriminate between the different members of the CDK family and inhibit also CDK5, which is not involved in cell cycle control. Testing a new class of CDK inhibitors, we find that inhibitory activity against CDK5, but not cell cycle-relevant CDKs, confers neuroprotection. Moreover, we demonstrate that cleavage of the CDK5 activator protein p35 to p25 is associated with CDK5 overactivation after focal cerebral ischemia, but not in other models used in this study. We find that blocking CDK5 activity, but not caspase inhibition, protects mitochondrial integrity of lesioned neurons. Thus, in our models, CDK5, rather than cell cycle-relevant CDKs, activates neuronal cell death pathways upstream of mitochondrial dysfunction, and inhibition of CDK5 may promote functional long-term rescue of injured neurons. Moreover, we present the first CDK5-selective small molecule inhibitor, lacking unwanted cytostatic effects due to cross-inhibition of mitotic CDKs.
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PMID:Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. 1457 69

c-Jun N-terminal protein kinase (JNK) activation and subsequent c-Jun phosphorylation which stimulates its transcriptional activity have been well studied in cerebral ischemia. To determine whether mitogen-activated protein kinase kinase 7 (MKK7) play a role in JNK activation in response to the stress of global cerebral ischemia, we tested the activation of such a kinase by using phospho-Ser and phospho-Thr antibodies. Immunoprecipitation and Western blot analysis revealed that MKK7 was expressed at similar levels in all conditions, whereas phospho-MKK7 was highly augmented from 1 to 5 days and reached its peak at 3 days after 15 min of ischemia. Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation experiments. Moreover, MKK7 activation was markedly reduced by pretreatment of the free radical scavenging thiol antioxidant N-acetylcysteine (NAC). Together with previous studies, the late activation of MKK7 in hippocampal CA1 region may contribute to delayed cell death, and the protective effects of antioxidant against ischemia-induced injury may be partially mediated by the down-regulation of JNK signal pathway.
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PMID:Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. 1457 11

The effect of transient focal cerebral ischemia on protein regulation was studied in mice using multiparametric immunohistochemistry. Injury was characterized by measurements of blood flow, regional protein synthesis and terminal transferase biotinylated-dUTP nick end labeling (TUNEL). The proteins studied were selected from a previously established list of differentially regulated proteins and included the GTPases dynamin, RhoB, CAS and Ran BP-1, the transcription factors Nurr1 and p-Stat 6, the protein kinase MAPK p49, the splicing factors SRPK1 and hPrp16, the cell cycle control proteins cyclin B1 and Nek2, the inflammatory proteins FKBP12 and Rag2, the cell adhesion protein paxillin and the folding protein TCP-1. Regulation patterns were diverse and comprised ipsi- and/or contralateral up- and down-regulation with or without topical association to impeding cell death. Some proteins (SRPK1, TCP-1 and Nurr1) also exhibited post-ischemic translocation from the nucleus to the cytosol. Our observations stress the importance of regional analysis for the interpretation of proteomic data, and contribute to the identification of new pathways that may be involved in the evolution of post-ischemic brain injury.
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PMID:Immunohistochemical analysis of protein expression after middle cerebral artery occlusion in mice. 1464 78

Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic (plasma glucose approximately 20 mM) and hypercapnic (paCO2) approximately 300 mm Hg) global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCgamma, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes, as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCgamma, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cingulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.
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PMID:Hyperglycemia and hypercapnia differently affect post-ischemic changes in protein kinases and protein phosphorylation in the rat cingulate cortex. 1467 11

The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.
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PMID:Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. 1471 58

Recent evidence suggests that activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Thus, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. In the current study, we report that a small molecule, AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile), which has been shown to inhibit the JNK signaling pathway, promotes cell survival after cerebral ischemia. In vivo, AS601245 (40, 60, and 80 mg/kg) administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) was also observed in rats after focal cerebral ischemia. These data suggest that the use of JNK inhibitors such as AS601245 may be a relevant strategy in the therapy of ischemic insults.
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PMID:AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. 1498 19

Oxidative damage to the endoplasmic reticulum (ER) could be involved in ischemic neuronal cell death because this organelle is susceptible to reactive oxygen species. Using wild-type mice and copper/zinc-superoxide dismutase (SOD1) transgenic mice, we induced focal cerebral ischemia and compared neuronal degeneration and ER stress, that is, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK). We found that neurons with severe and prolonged phosphorylation of eIF2alpha and PERK underwent later degeneration, and that this was partially prevented by SOD1 overexpression. Signals for superoxide production and phospho-PERK were colocalized, which further indicates a pivotal role for superoxide in ER damage. We investigated the molecular mechanisms of oxidative ER stress and found that detachment of glucose-regulated protein 78 from PERK was the key step. We conclude that ER damage is involved in oxidative neuronal injury in the brain after ischemia/reperfusion.
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PMID:Oxidative injury to the endoplasmic reticulum in mouse brains after transient focal ischemia. 1500 93


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