Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kainic acid, an analogue of glutamate, causes limbic seizures and induces cell death in the rat brain. We examined the activation of MAPK family kinases; ERKs, JNKs and p38 kinase in rat hippocampus after KA treatment. Activation of all three kinases were observed at 30 min after the treatment, but, in contrary to ERK phosphorylation, which lasted up to 3 h, the phosphorylation of JNK and p38 returned to the basal level by 2 h. The phosphorylation of' upstream kinases for the MAPK family was distinct. The phosphorylation of MEK1 clearly increased at 30 min but diminished rapidly thereafter. The phosphorylation of MKK6 was also increased but reached peak at 2 h after KA treatment. However, the phosphorylation of other upstream kinases, SEK1 and MKK3, gradually decreased to 3 h after KA treatment. These results indicate that the KA activates all of the three MAPK family kinases with different time patterns and suggest the possibility that MKK3 and MKK6, and SEK1 may not be the upstream kinases for p38 and JNK in rat hippocampus.
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PMID:Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure. 1119 Feb 75

Proneurotrophins bind with high affinity to p75 neurotrophin receptor (p75NTR) and lack the capacity to bind Trk receptors, suggesting that proneurotrophins can elicit apoptosis via p75NTR even in cells expressing survival-promoting Trk receptors. In the CNS, basal forebrain (BF) neurons are particularly vulnerable to degeneration in Alzheimer's disease, and are among the few populations of brain neurons that express p75NTR throughout life. These neurons also express Trk receptors and may be concomitantly exposed to both proneurotrophins and mature neurotrophins during development, disease, or after injury. We investigated the interaction of mature and proneurotrophin signaling in these CNS neurons. Kainic acid-induced seizures elicited production of pro-NGF by BF astrocytes before caspase activation in p75NTR-positive BF neurons, demonstrating local production of proneurotrophins under pathological conditions and suggesting apoptotic signaling in vivo. Mechanisms of proneurotrophin-induced death were analyzed in cultured BF neurons, and required both p75NTR and its coreceptor sortilin. Surprisingly, exposure to both mature neurotrophins and proneurotrophins demonstrated that Trk phosphorylation did not prevent pro-NGF-induced apoptosis via p75NTR. However, activation of PI3K (phosphatidylinositol 3-kinase)/Akt and MEK (mitogen-activated protein kinase kinase)/Erk pathways prevented pro-NGF-induced apoptosis, revealing a novel critical checkpoint in survival versus apoptotic signaling downstream of Trk activation, and suggesting that pro-NGF blocks survival signaling by preventing Akt and Erk activation. This study shows that proneurotrophins are produced in the brain under pathological conditions, and can elicit apoptosis of BF neurons even when Trk receptors are activated.
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PMID:Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. 1685 3

Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose)-polymerase (PARP). The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex. Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK3 isoform in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection.
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PMID:The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. 2220 97