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)

Activation of Akt/protein kinase B has been recently reported to play an important role in ischemic tolerance. We here demonstrate that the decreased protein expression and phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) underlie the increased Akt-Ser-473 phosphorylation in the hippocampal CA1 subfield in ischemic preconditioning (IPC). Co-immunoprecipitation analysis reveals that Akt physically interacts with Rac1, a small Rho family GTPase required for mixed lineage kinase 3 (MLK3) autophosphorylation, and both this interaction and Rac1-Ser-71 phosphorylation induced by Akt are promoted in preconditioned rats. In addition, we show that Akt activation results in the disassembly of the plenty of SH3s (POSH)-MLK3-Rac1 signaling complex and down-regulation of the activation of MLK3/c-Jun N-terminal kinase (JNK) pathway. Akt activation results in decreased serine phosphorylation of 14-3-3, a cytoplasmic anchor of Bax, and prevents ischemia-induced mitochondrial translocation of Bax, release of cytochrome c, and activation of caspase-3. The expression of Fas ligand is also decreased in the CA1 region. Akt activation protects against apoptotic neuronal death as shown in TUNEL staining following IPC. Intracerebral infusion of LY294002 before IPC reverses the increase in Akt phosphorylation and the decrease in JNK signaling activation, as well as the neuroprotective action of IPC. Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance.
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PMID:Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. 1697 99

Our previous studies showed that the assembly of the GluR6-PSD95-mixed lineage kinase 3 (MLK3) signaling module played an important role in rat ischemic brain injury. In this study, we aimed to elucidate whether ischemic preconditioning could downregulate the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK4/7, and c-Jun N-terminal kinase (JNK). As a result, ischemic preconditioning could not only inhibit the assembly of the GluR6-PSD95-MLK3 signaling module, diminish the phosphorylation of the transcription factor c-Jun, downregulate Fas ligand expression, attenuate the phosphorylation of 14-3-3 and Bcl-2 and the translocation of Bax to mitochondria, but also increase the release of cytochrome c and the activation of caspase-3. In contrast, both GluR6 antisense ODNs (oligodeoxynucleotides) and 6,7,8,9-tetrahydro-5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime (NS102), an antagonist of GluR6 receptor, prevented the above effects of preconditioning, which shows that suppressing the expression of GluR6 or inhibiting GluR6 activity contributes negatively to preconditioning-induced ischemia tolerance. Taken together, our results indicate that preconditioning can inhibit the over-assembly of the GluR6-PSD95-MLK3 signaling module and the JNK3 activation. GluR6 subunit-containing kainite receptors play an important role in the preconditioning-induced neuronal survival and provide new insight into stroke therapy.
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PMID:Neuroprotection of preconditioning against ischemic brain injury in rat hippocampus through inhibition of the assembly of GluR6-PSD95-mixed lineage kinase 3 signaling module via nuclear and non-nuclear pathways. 1932 23

Although previous researches indicated that heme oxygenase-1 (HO-1) plays a conspicuous role in neuronal injury induced by reperfusion following the brain ischemia, reasonable mechanisms for the role of HO-1 are not clear. In this work, we investigated whether HO-1 was involved in the regulation of the c-Jun N-terminal kinase (JNK) signaling pathway and neuronal cell injury induced by the brain ischemia followed by reperfusion. Cobaltic protoporphyrin (CoPP), an activator of HO-1, was administrated to induce the overexpression of HO-1 by intracerebroventricular infusion 20 min before ischemia. The results showed that the combination of HO-1-mixed lineage kinase 3 (MLK3), MLK3-mitogen-activated kinase kinase 7 (MKK7) and MKK7-JNK3 increased to a peak at 6h of reperfusion following 15 min of ischemia induced by four-vessel occlusion in rats, and these effects were downregulated by CoPP. In addition, CoPP could inhibit the activation of JNK3, c-Jun and caspase-3. Furthermore, pretreatment with CoPP significantly increased the survival of neurons after 5 days of reperfusion. In contrast, all of the above effects of CoPP were reversed by zinc protoporphyrin (ZnPP), a selective inhibitor of HO-1. Our results suggested that HO-1 could protect neurons against brain ischemic injury by downregulating the JNK signaling pathway through the MLK3-MKK7-JNK3 signaling module.
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PMID:Heme oxygenase-1 regulates the JNK signaling pathway through the MLK3-MKK7-JNK3 signaling module in brain ischemia injury. 2208 22

Fasudil hydrochloride (FH), a Rho kinase (ROCK) inhibitor, has been reported to prevent cerebral ischemia in vivo from increasing cerebral blood flow and inhibiting inflammatory responses. However, it is uncertain by what mechanism a ROCK inhibitor can directly protect neurons against ischemic damage. The present study was designed to evaluate whether FH decreased the increased phosphorylation of glutamate receptor 6 (GluR6) and its downstream in GluR6-MLK3-JNKs signal transduction pathway following global transient cerebral ischemia, as a result of protecting against neuronal apoptosis and death. Transient cerebral ischemia was induced by the Pulsinelli-Brierley four-vessel occlusion method. FH (15 mg/kg) was administered to rats by intraperitoneal injection 30 min before ischemia. The phosphorylation and protein expression of GluR6 at 6 h during reperfusion were detected using immunoprecipitation and immunoblotting analysis. The phosphorylation and protein expression of Mixed lineage kinase 3 (MLK3) at ischemia/reperfusion (I/R) 6 h and c-Jun N-terminal kinase (JNK) at I/R 3 d were detected using immunoblotting analysis, respectively. The same method was used to detect the expression of caspase-3 at I/R 6 h. Furthermore, we also use TUNEL staining and Cresyl violet staining to examine the survival neurons in rat hippocampal CA1 regions after 3 and 5 d reperfusion, respectively. Our study indicated that FH could inhibit the increased phosphorylation of GluR6 and MLK3 and the expression of caspase-3 at peaked 6 h of reperfusion and the phosphorylation of JNK (3 d) (p < 0.5). The results of TUNEL staining and Cresyl violet showed that the number of surviving pyramidal neurons in rats hippocampal CA1 subfield increased markedly in FH-treated rats compared with ischemic groups after 3 or 5 d of reperfusion following ischemia (p < 0.5). These results suggested that FH, as a ROCK inhibitor, may be partly responsible for its protective effects against such damage by taking part in GluR6-MLK3-JNKs signaling pathway which modulates ischemic damage. Taken together, this is the first study investigating Rho and ROCK as the upstream of GluR6 taking part in GluR6-MLK3-JNKs signal transduction pathway following cerebral ischemia.
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PMID:Fasudil hydrochloride protects neurons in rat hippocampal CA1 region through inhibiting GluR6-MLK3-JNKs signal pathway. 2479 42