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)

To investigate the role of the Egr family of transcription regulatory factors in neuronal apoptosis, we examined the effect of a dominant negative Egr inhibitor construct in a well characterized in vitro paradigm, cerebellar granule cell death induced by withdrawal of depolarizing concentrations of extracellular potassium. We found that this apoptotic stimulus increases the activity of a reporter gene driven by the Egr response element and that a dominant negative inhibitor of Egr-mediated transcription blocks granule cell apoptosis. In contrast, apoptosis of immature granule cells induced by cytosine arabinoside is not inhibited by the Egr inhibitor construct. Because activation of c-Jun is an essential step in granule cell death induced by potassium deprivation, but not cytosine arabinoside, we asked whether the Egr inhibitor acts by influencing c-Jun activation or its ability to induce apoptosis. We found that the Egr inhibitor does not block the ability of a constitutively active c-Jun construct to induce apoptosis in these cells but does suppress activation of c-Jun-mediated transcription induced by lowering extracellular potassium concentration. Furthermore, the Egr inhibitor blocks the ability of MEKK1 [mitogen-activated protein kinase (MAPK) kinase kinase 1], an upstream kinase capable of stimulating the JNK (c-Jun N-terminal protein kinase)-c-Jun pathway, to induce apoptosis and activate c-Jun. Together, these studies indicate that the Egr family of transcription factors plays a critical role in neuronal apoptosis and identify c-Jun activation as an important downstream target of the Egr family in this process.
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PMID:A dominant negative inhibitor of the Egr family of transcription regulatory factors suppresses cerebellar granule cell apoptosis by blocking c-Jun activation. 1148 12

Vinblastine and other microtubule-damaging agents, such as nocodazole and paclitaxel, cause cell cycle arrest at the G2/M transition and promote apoptosis in eukaryotic cells. The roles of these drugs in disrupting microtubule dynamics and causing cell cycle arrest are well characterized. However, the mechanisms by which these agents promote apoptosis are poorly understood. We disrupted the MEKK1 kinase domain in chicken bursal B-cell line DT40 by homologous recombination and have shown that it is essential for both vinblastine-mediated apoptosis and vinblastine-mediated c-Jun N-terminal protein kinase activation. In addition, our data indicate that vinblastine-mediated apoptosis in DT40 cells requires new protein synthesis but does not require G2/M arrest, suggesting that vinblastine-mediated cell cycle arrest and apoptosis are two independent processes.
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PMID:MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption. 1158 1

The protein serine-threonine kinase Akt mediates cell survival signaling initiated by various growth-promoting factors such as insulin. Here we report that SEK1 is a target of Akt in intact cells. Insulin inhibited the anisomycin-induced stimulation of both endogenous SEK1 and its substrate c-Jun N-terminal kinase (JNK), but not that of the upstream kinase MEKK1, in 293T cells. The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002. Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation, but not that of MEKK1, in transfected 293T cells. Co-immunoprecipitation analysis revealed that endogenous Akt physically interacted with endogenous SEK1 in cells and that this interaction was promoted by insulin. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition. Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A). Taken together, these results suggest that Akt suppresses stress-activated signaling by targeting SEK1.
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PMID:Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. 1170 64

Axin uses different combinations of functional domains in down-regulation of the Wnt pathway and activation of the MEKK1/JNK pathway. We are interested in the elucidation of the functional switch of Axin. In the present study, we show that the Wnt activator CKIepsilon, but not CKIIalpha, Frat1, LRP5, or LRP6, inhibited Axin-mediated JNK activation. We also found that both CKIalpha and CKIepsilon interacted with Axin, whereas CKIIalpha did not bind to Axin and had no effect on Axin-mediated JNK activity even though CKIIalpha has also been suggested to be an activator for the Wnt pathway. The COOH-terminal region and the MEKK1-interacting domain of Axin are important for CKIalpha-Axin and CKIepsilon-Axin interaction. We further demonstrated that CKIepsilon and CKIalpha binding to Axin excluded MEKK1 binding, indicating that a competitive physical occupancy may underlie the inhibitory effect. Moreover, our data indicated that CKIepsilon kinase activity plays an additive role in this effect. Taken together, we have demonstrated that CKI and CKII exhibit differential effects on Axin-MEKK1 interaction and Axin-mediated JNK activation. Furthermore, our data suggest that CKI may provide a possible switch mechanism for Axin function in the regulation of Wnt and JNK pathways.
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PMID:Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways. 1188 95

Monoamine oxidases (MAO) A and B deaminate a number of biogenic amines. Aberrant expression of MAO is implicated in several psychiatric and neurogenerative disorders. In this study, we have shown that phorbol 12-myristate 13-acetate (PMA) increases human MAO B, but not MAO A, gene expression. The sequence between -246 and -225 bp consists of overlapping binding sites (Sp1/Egr-1/Sp1) that are recognized by Sp1, Sp3, and PMA-inducible Egr-1 is essential for PMA activation. PMA transiently increases egr-1 and c-jun gene expression. Mutation studies show that Egr-1 and c-Jun transactivate the MAO B promoter and increase endogenous MAO B transcripts via the Sp1/Egr-1/Sp1 overlapping binding sites. Sp3 inhibits Sp1 and Egr-1 activation of MAO B gene expression. c-fos gene expression was increased by PMA but not involved in MAO B gene transcription. Furthermore, protein kinase C inhibitor blocks the PMA-dependent activation of MAO B. Co-transfection of the MAO B promoter with dominant negative forms of Ras, Raf-1, MEKK1, MEK1, MEK3, MEK7, ERK2, JNK1, and p38/RK inhibit the PMA-dependent activation of the MAO B promoter. These results indicate that MAO B expression is selectively induced by the activation of protein kinase C and MAPK signaling pathway and that c-Jun and Egr-1 appear to be the ultimate targets of this regulation.
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PMID:Activation of human monoamine oxidase B gene expression by a protein kinase C MAPK signal transduction pathway involves c-Jun and Egr-1. 1195 20

IFN-gamma induces a number of genes to up-regulate cellular responses by using specific transcription factors and the cognate elements. We recently discovered that CCAAT/enhancer-binding protein-beta (C/EBP-beta) induces gene transcription through an IFN-response element called gamma-IFN-activated transcriptional element (GATE). Using mutant cells, chemical inhibitors, and specific dominant negative inhibitors, we show that induction of GATE-driven gene expression depends on MEK1 (mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase) and ERKs (extracellular signal-regulated protein kinases) but is independent of Raf-1. Interestingly in cells lacking the MEKK1 gene or expressing the dominant negative MEKK1, ERK activation, and GATE dependent gene expression is inhibited. A dominant negative MEKK1 blocks C/EBP-beta-driven gene expression stimulated by IFN-gamma. These studies describe an IFN-gamma-stimulated pathway that involves MEKK1-MEK1-ERK1/2 kinases to regulate C/EBP-beta-dependent gene expression.
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PMID:MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma. 1204 45

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. 1205 37

Proteolytic modification of certain key regulatory molecules involved in apoptotic and prosurvival pathways may be a feature of the control of programmed cell death. Four molecules of the Bd-2 family (BID, Bcl-2, Bax, Bcl-X(L)) have been reported to be deaved during apoptosis, as has a cellular inhibitor of apoptosis (XIAP). Two proteins involved in NF-kappaB activation, RIP and TRAF1, are cleaved during apoptosis induced by agents that activate both pathways. MEKK1, a molecule involved in a protein kinase stress signaling cascade that contributes to apoptosis and NF-kappaB activation, also undergoes cleavage. In each case, the cleavage products may result in the inactivation of a former function or the gaining of a new function, thus contributing to the delicately balanced regulation of apoptosis.
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PMID:Proteolytic cleavage of molecules involved in cell death or survival pathways: a role in the control of apoptosis? 1206 67

Mammalian MAP/ERK kinase kinase 1 (MEKK1) was identified as a mammalian homolog of Ste11p of the yeast pheromone-induced mating pathway. Like Ste11p, MEKK1 is a MAP3 kinase linked to at least two MAP kinase cascades and regulatory events that require cytoskeletal reorganization. MEKK1 is activated by molecules that impact cytoskeletal function. MEKK1-/-cells are defective in cell migration, demonstrating that it is required for cell motility. MEKK1 has a 1,200 residue N-terminal regulatory domain that interacts with a dozen identified proteins. Using part of the MEKK1 N-terminus in a yeast two-hybrid screen, we discovered a novel interaction with p115 Rho GTPase-activating protein (GAP). The p115 Rho GAP binds to MEKK1 in vitro and in intact cells. The p115 Rho GAP has selectivity for RhoA over other Rho family members. Expression of p115 Rho GAP reduces MEKK1-induced signaling to AP-1. The reduced activation of AP-1 is dependent on the association of MEKK1 with p115 Rho GAP, because deletion of the Rho GAP SH3 domain, which abrogates their interaction, restores the stimulatory effect of MEKK1 on AP-1 activity. Here we have identified an MEKK1 binding partner that offers a connection between this protein kinase and the machinery regulating cytoskeletal reorganization.
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PMID:p115 Rho GTPase activating protein interacts with MEKK1. 1211 26

The cellular response to genotoxic stress includes activation of protein kinase Cdelta (PKCdelta). The functional role of PKCdelta in the DNA damage response is unknown. The present studies demonstrate that PKCdelta is required in part for induction of the stress-activated protein kinase (SAPK/JNK) in cells treated with 1-beta-d-arabinofuranosylcytosine (araC) and other genotoxic agents. DNA damage-induced SAPK activation was attenuated by (i) treatment with rottlerin, (ii) expression of a kinase-inactive PKCdelta(K-R) mutant, and (iii) down-regulation of PKCdelta by small interfering RNA (siRNA). Coexpression studies demonstrate that PKCdelta activates SAPK by an MKK7-dependent, SEK1-independent mechanism. Previous work has shown that the nuclear Lyn tyrosine kinase activates the MEKK1 --> MKK7 --> SAPK pathway but not through a direct interaction with MEKK1. The present results extend those observations by demonstrating that Lyn activates PKCdelta, and in turn, MEKK1 is activated by a PKCdelta-dependent mechanism. These findings indicate that PKCdelta functions in the activation of SAPK through a Lyn --> PKCdelta --> MEKK1 --> MKK7 --> SAPK signaling cascade in response to DNA damage.
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PMID:Activation of SAPK/JNK signaling by protein kinase Cdelta in response to DNA damage. 1237 81


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