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:2.7.11.25 (MEKK1)
1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently obtained evidence that treatment of human colon cancer cells with exisulind (sulindac sulfone) and related compounds induces apoptosis by activation of protein kinase G (PKG) and c-Jun kinase (JNK1). The present study further explores this mechanism. We demonstrate that in NIH3T3 cells a constitutively active mutant of PKG causes a dose-dependent activation of JNK1 and thereby transactivates c-Jun and stimulates transcription from the AP-1 enhancer element. The activation of JNK1 and the transactivation of c-Jun by this mutant of PKG were inhibited by a dominant negative MEKK1. In vitro assays showed that a purified PKG directly phosphorylated the N-terminal domain of MEKK1. PKG also directly phosphorylated a full-length MEKK1, and this was associated with enhanced MEKK1 phosphorylation. Thus, it appears that PKG activates JNK1 through a novel PKG-MEKK1-SEK1-JNK1 pathway, by directly phosphorylating and activating MEKK1.
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PMID:Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1. 1127 63

Our previous studies have shown that MMP-9 levels are significantly elevated during the progression of human gliomas. In the current study, we examined the role of JNK- and ERK-dependent signaling modules in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which JNK/ERK1 is constitutively activated. SNB19 cells that were transfected with dominant-negative JNK, MEKK, and ERK1 expression vectors showed reduced MMP-9 promoter activity. In addition, conditioned medium collected from SNB19 cells transfected with these expression vectors showed diminished MMP-9 activity in the presence of phorbol myristate acetate, as determined by gelatin zymography. The cotransfection of SNB19 cells with kinase-deficient c-raf also diminished MMP-9 promoter activity. Further, in the presence of a specific inhibitor of MEKK (PD098059), the Matrigel invasion assay showed the invasiveness of dominant-negative SNB19 cells transfected with dominant-negative JNK1 or ERK1 to be remarkably reduced. In conclusion, our studies showed for the first time that MMP-9 production and the invasive behavior of SNB 19 cells are regulated by JNK- and ERK-dependent signaling modules and that interfering with either of the pathways reduces invasiveness.
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PMID:Regulation of MMP-9 (type IV collagenase) production and invasiveness in gliomas by the extracellular signal-regulated kinase and jun amino-terminal kinase signaling cascades. 1131 98

Cystatin A, a cysteine proteinase inhibitor, is a cornified cell envelope constituent expressed in the upper epidermis. We previously reported that a potent protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate, increases human cystatin A expression by the activation of AP-1 proteins. Here, we delineate the signaling cascade responsible for this regulation. Co-transfection of the cystatin A promoter into normal human keratinocytes together with a dominant active form of ras increased the promoter activity by 3-fold. In contrast, a dominant negative form of ras suppressed basal cystatin A promoter activity. Further analyses disclosed that transfection of dominant negative forms of raf-1, MEK1, ERK1, ERK2, or wild-type MEKK1 all increased cystatin A promoter activity in normal human keratinocytes, whereas wild-type raf-1, ERK1, ERK2, or dominant negative forms of MEKK1, MKK7, or JNK1 suppressed the promoter activity. The increased or decreased promoter activity reflected the expression of cystatin A on mRNA and protein levels. These effects were not observed when a cystatin A promoter with a T2 (-272 to -278) deletion was used. In contrast, transfection of dominant negative forms of MKK3, MKK4, or p38 did not affect cystatin A promoter activity. Immunohistochemical analyses revealed that phosphorylated active extracellular signal-regulated kinases and c-Jun N-terminal kinase were expressed in the nuclei of basal cells and cells in the suprabasal-granular cell layer, respectively. These results indicate that the expression of cystatin A is regulated via mitogen-activated protein kinase pathways positively by Ras/MEKK1/MKK7/JNK and negatively by Ras/Raf/MEK1/ERK.
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PMID:Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. 1145 47

Vascular endothelial growth factor (VEGF) plays an essential role in the initiation and regulation of angiogenesis-a crucial component of wound healing and cancer growth. Prostaglandins (PGs) stimulate angiogenesis but the precise mechanisms of their pro-angiogenic actions remain unexplained. We investigated whether prostaglandin E(2) (PGE(2)) can induce VEGF expression in rat gastric microvascular endothelial cells (RGMEC) and the signaling pathway(s) involved. We demonstrated that PGE(2) significantly increased ERK2 and JNK1 activation and VEGF mRNA and protein expression. Incubation of RGMEC with PD 98059 (MEK kinase inhibitor) significantly reduced PGE(2)-induced ERK2 activity, VEGF mRNA and protein expression. Furthermore, PD 98059 treatment almost completely abolished JNK1 activation. Our data suggest that PGE(2)-stimulates VEGF expression in RGMEC via transactivation of JNK1 by ERK2. One potential implication of this finding is that increased PG levels in cancers could facilitate tumor growth by stimulating VEGF synthesis and angiogenesis.
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PMID:PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. 1152 87

Galpha13 mediates the ability of the morphogen retinoic acid to promote primitive endoderm formation from mouse P19 embryonal carcinoma stem cells, a process that includes the obligate activation of Jun N-terminal kinase. Expression of the constitutively activated (Q226L) GTPase-deficient form of Galpha13 mimics retinoic acid and was used to investigate the signaling upstream of primitive endoderm formation. Jun N-terminal kinase 1 activity, MEK1,2, MKK4, and MEKK1 were constitutively activated in clones stably transfected to express Q226L Galpha13. Dominant negative forms of MEKK1 and MEKK4 were expressed stably in the clones harboring Q226L Galpha13. Expression of dominant negative versions of either MEKK1 or MEKK4 effectively blocks both the activation of Jun N-terminal kinase as well as the formation of primitive endoderm. Depletion of MEKK1, -2, or -4 by antisense oligodeoxynucleotides suppressed signaling from Q226L Galpha13 to JNK1 and primitive endoderm formation. We demonstrate that the signal linkage map from Galpha13 activation to primitive endoderm formation in these stem cells requires activation at three levels of the mitogen-activated protein kinase cascade: MEKK1, -2, or -4 for MAP kinase kinase kinase; MKK4 and/or MEK1 for MAP kinase kinase; and JNK1 for MAP kinase.
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PMID:Expression of Galpha 13 (Q226L) induces P19 stem cells to primitive endoderm via MEKK1, 2, or 4. 1170 Mar 6

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

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

Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH(2)-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
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PMID:Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. 1206 26

Nitrogen oxides (NOx) are important indoor air pollutants and an occupational hazard. Many studies demonstrated that NOx causes lung tissue damage based on the oxidation properties and the free-radical potentials of these gases. In this study we found that NOx delivered as a NO gas-saturated solution induced proliferation of human lung fibroblast MCR-5 cells as evidenced by increasing cell number and S phase distribution. Western data showed that NOx increased the expressions of c-Fos, c-Jun, and signaling kinases including MEKK1, JNK1, and p38 (with induction fold of 3.3, 2.8, and 3.2, respectively) in the cells 12 h after treatment. The levels of phospho-MEKK1 and phospho-JNK1 were also increased. The application of iNOS inhibitor, NAME, partially blocked the activation of MEKK4 and JNK1. These data suggested that JNK and p38 signaling kinases are activated partly by endogenous NO that are generated from NOx-activated iNOS in MRC-5 cells. Therefore, the NOx-induced cell proliferation via activation of MEKK1, JNK1, and p38 might contribute to lung tissue damage caused by NOx pollutants.
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PMID:Induced proliferation of human MRC-5 cells by nitrogen oxides via direct and indirect activation of MEKK1, JNK, and p38 signals. 1207 29

In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1-30 microM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31-8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1-binding element, but not that element responsive to nuclear factor (NF)-IL-6 or NF-kappaB, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited kappaB activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.
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PMID:Proteasome inhibitors stimulate interleukin-8 expression via Ras and apoptosis signal-regulating kinase-dependent extracellular signal-related kinase and c-Jun N-terminal kinase activation. 1215 16


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