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: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (alpha, beta, and gamma isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7alpha isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7alpha isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7beta and MKK7gamma isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that the MKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.
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PMID:The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. 989 Oct 90

We tested the coupling of endothelin receptors to mitogen-activated protein kinases (MAPK) and nuclear factor c-Jun in intact canine pulmonary artery smooth muscle. Muscle rings denuded of endothelium were stimulated with 10(-7)M ET-1 and frozen during contraction. An <<in-gel>> kinase assay with myelin basic protein as substrate revealed protein kinase activities at 98, 75, 55, 50, 44 and 40 kDa. Erk1 and Erk2 MAPK were activated by ET-1 to 5.4+/-0.97 and 4.03+/-1. 54 times basal activity at 10 min. Using phospho-specific antibodies, we found increased threonine/tyrosine phosphorylation of p38 and JNK1 MAPK to 2.04+/-0.47 and 2.56+/-0.72 times basal. ET-1 increased the phosphorylation level of nuclear factor c-Jun with a time-course closely matching the activation of JNK1 and p38 MAPK. Therefore, endothelin receptors initiate intracellular signals leading to activation of Erk, p38 and JNK1 MAPK pathways and ultimately to nuclear targets. The activation of JNK1 MAPK seems closely related to the phosphorylation of nuclear transcription factor c-Jun.
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PMID:Endothelin-1 activates MAP kinases and c-Jun in pulmonary artery smooth muscle. 991 57

Collagenase-1 (matrix metalloproteinase-1, MMP-1) is expressed by several types of cells, including fibroblasts, and apparently plays an important role in the remodeling of collagenous extracellular matrix in various physiologic and pathologic situations. Here, we have examined the molecular mechanisms of the activation of fibroblast MMP-1 gene expression by a naturally occurring non-phorbol ester type tumor promoter okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatase 2A. We show that in fibroblasts OA activates three distinct subgroups of mitogen activated protein kinases (MAPKs): extracellular signal-regulated kinase1,2 (ERK1,2), c-Jun N-terminal-kinase/stress-activated protein kinase (JNK/SAPK) and p38. Activation of MMP-1 promoter by OA is entirely blocked by overexpression of dual-specificity MAPK phosphatase CL100. In addition, expression of kinase-deficient forms of ERK1,2, SAPKbeta, p38, or JNK/SAPK kinase SEK1 strongly inhibited OA-elicited activation of MMP-1 promoter. OA-elicited enhancement of MMP-1 mRNA abundance was also strongly prevented by two chemical MAPK inhibitors: PD 98059, a specific inhibitor of the activation of ERK1,2 kinases MEK1,2; and SB 203580, a selective inhibitor of p38 activity. Results of this study show that MMP-1 gene expression in fibroblasts is coordinately regulated by ERK1,2, JNK/SAPK, and p38 MAPKs and suggest an important role for the stress-activated MAPKs JNK/SAPK and p38 in the activation of MMP-1 gene expression. Based on these observations, it is conceivable that specific inhibition of stress-activated MAPK pathways may serve as a novel therapeutic target for inhibiting degradation of collagenous extracellular matrix.
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PMID:Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38. 992 49

POU domain proteins have been implicated as key regulators during development and lymphocyte activation. The POU domain protein T-cell factor beta1 (TCFbeta1), which binds octamer and octamer-related sequences, is a potent transactivator. In this study, we showed that TCFbeta1 is phosphorylated following activation via the T-cell receptor or by stress-induced signals. Phosphorylation of TCFbeta1 occurred predominantly at serine and threonine residues. Signals which upregulate Jun kinase (JNK)/stress-activated protein kinase activity also lead to association of JNK with TCFbeta1. JNK associates with the activation domain of TCFbeta1 and phosphorylates its DNA binding domain. The phosphorylation of recombinant TCFbeta1 by recombinant JNK enhances the ability of TCFbeta1 to bind to a consensus octamer motif. Consistent with this conclusion, TCFbeta1 upregulates reporter gene transcription in an activation- and JNK-dependent manner. In addition, inhibition of JNK activity by catalytically inactive MEKK (in which methionine was substituted for the lysine at position 432) also inhibits the ability of TCFbeta1 to drive inducible transcription from the interleukin-2 promoter. These results suggest that stress-induced signals and T-cell activation induce JNK, which then acts on multiple cis sequences by modulating distinct transactivators like c-Jun and TCFbeta1. This demonstrates a coupling between the JNK activation pathway and POU domain proteins and implicates TCFbeta1 as a physiological target in the JNK signal transduction pathway leading to coordinated biological responses.
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PMID:Jun kinase phosphorylates and regulates the DNA binding activity of an octamer binding protein, T-cell factor beta1. 1002 89

1. Cultured cerebellar granule neurons maintained in medium containing 26 mM potassium (high K+ or HK+) undergo cell death when switched to medium with 5 mM potassium (low K+ or LK+). This low K(+)-induced cell death has typical features of apoptosis. The intracellular signaling pathway of low K(+)-induced apoptosis has been investigated. 2. Cerebellar granule neurons become committed to undergo apoptosis between 2 and 5 h after K+ deprivation, judging from the inability of high K+ to rescue them after this time. Although the levels of most mRNAs decrease markedly concomitant with commitment, expression of c-jun mRNA increases 2-3 h after K+ deprivation. Among the family of caspases, a caspase-3-like protease is activated within 4 h of lowering the K+ concentration. A caspase-1-like protease is also activated within 2 h of K+ deprivation. 3. Inhibition of phosphatidylinositol 3-kinase (PI3-K) activity by LY294002 or wortmannin also induces apoptosis in cerebellar granule neurons. The intracellular signaling pathway of LY294002-induced apoptosis has been investigated. The activity of c-Jun N-terminal kinase (JNK) increases 8 h after addition of LY294002 to high K+ medium or low K+ medium containing BDNF. Expression of c-Jun protein also increases almost simultaneously. 4. The low K(+)-induced apoptosis of cerebellar granule neurons is prevented by high K+ (membrane depolarization by high K+), BDNF, IGF-1, bFGF or cAMP. The intracellular signaling pathways by which these agents prevent low K(+)-induced apoptosis have been investigated. Agents other than cAMP prevent apoptosis through PI3-K and a Ser/Thr kinase, Akt/PKB. The survival-promoting effect of cAMP does not depend on the PI3-K-Akt pathway.
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PMID:[Apoptosis-inducing and -preventing signal transduction pathways in cultured cerebellar granule neurons]. 1008 75

SPI-B is a B lymphocyte-specific Ets transcription factor that shares a high degree of similarity with PU.1/SPI-1. In direct contrast to PU.1(-/-) mice that die in utero and lack monocytes, neutrophils, B cells, and T cells, Spi-B-/- mice are viable and exhibit a severe B cell proliferation defect. Since PU.1 is expressed at wild type levels in Spi-B-/- B cells, the mutant mice provide genetic evidence that SPI-B and PU.1 have at least some non-redundant roles in B lymphocytes. To begin to understand the molecular basis for these defects, we delineated functional domains of SPI-B for comparison to those of PU.1. By using a heterologous co-transfection system, we identified two independent transactivation domains in the N terminus of SPI-B. Interestingly, only one of these domains (amino acids 31-61), a proline/serine/threonine-rich region, unique among Ets proteins, is necessary for transactivation of the immunoglobulin lambda light chain enhancer. This transactivation motif is in marked contrast to PU.1, which contains acidic and glutamine-rich domains. In addition, we describe a functional PU.1 site within the c-FES promoter which SPI-B fails to bind efficiently and transactivate. Finally, we show that SPI-B interacts with the PU.1 cofactors Pip, TBP, c-Jun and with lower affinity to nuclear factor interleukin-6beta and retinoblastoma. Taken together, these data suggest that SPI-B binds DNA with a different affinity for certain sites than PU.1 and harbors different transactivation domains. We conclude that SPI-B may activate unique target genes in B lymphocytes and interact with unique, although currently unidentified, cofactors.
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PMID:SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1. 1019 96

Mixed lineage kinases (MLKs) form a family of serin/threonine protein kinases with multiple protein/protein interaction domains (SH3, Cdc42 Rac interactive binding sequence, leucine zipper, and proline rich region), the physiological roles of which are largely unknown. We show that overexpression of wild type MLK3 leads to morphological transformation of NIH 3T3 fibroblasts and growth in soft agar. Consistent with this transforming potential, we demonstrate that MLK3 strongly induces transcription from a reporter construct that is driven by a composite AP-1-/Ets-1-enhancer element in HEK 293 cells. In the same cell system, MLK3 preferentially activates the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) mitogen-activated protein kinase cascade and to a lesser degree the extracellular signal-regulated kinase (ERK) pathway. Activation of the latter can be further enhanced by coexpression of wild type MEK1 and is blocked by the synthetic MEK inhibitor PD 098059 or a kinase-dead MEK1 mutant. Immunoprecipitated MLK3 catalyses the phosphorylation of MEK1 in vitro, but this phosphorylation leads only to a marginal activation. In support of these data, we also show that MEK1 is highly phosphorylated in vivo on Ser 217/221 in MLK3-transformed fibroblasts, whereas activating ERK phosphorylations are barely detectable. Nevertheless, MLK3-transformed NIH 3T3 fibroblasts are partially reverted when activation of MEK is specifically blocked with PD 098059. Our combined data show that although MLK3 is primarily an activator of the JNK/SAPK pathway, overexpression of the wild type protein leads to a transformed phenotype in NIH 3T3 cells that can be partially reversed by a synthetic MEK inhibitor. We conclude that the ERK pathway is necessary for MLK3-mediated transformation.
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PMID:The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. 1023 8

We reported previously that activation of endogenous activator protein 1 (AP-1) in chicken embryo fibroblasts is essential for the cellular transformation induced by v-src, and we further showed that the activation of AP-1 is accompanied by elevation of Fra-2 and c-Jun expression and also high-level phosphorylation of Fra-2 by activated endogenous extracellular signal-regulated kinase [mitogen-activated protein kinase (MAPK)]. Here, we report that the transcriptional activity of Fra-2/c-Jun heterodimer was greatly enhanced by cotransfecting a constitutively active mutant of MEK1 gene (MEK-DD) into F9 cells, indicating that Fra-2 was converted into an active transactivator after phosphorylation by MAPK. High-level expression of MEK-DD alone was sufficient to induce clear cellular transformation of chicken embryo fibroblasts, which caused constitutive activation of endogenous MAPK, hyperphosphorylation of Fra-2, and elevation of fra-2 and c-jun gene expression. These results indicate that phosphorylation of Fra-2 by MAPK plays an important role in stimulating endogenous AP-1 activity in a positive autoregulation mechanism, in which phosphorylated Fra-2 induces fra-2 expression through AP-1 binding sites present in its promoter. We also localized the Fra-2 phosphorylation sites by MAPK to three threonine and three serine residues in the COOH-terminal region by means of site-directed mutagenesis and showed that the threonine residues were more susceptible to MAPK.
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PMID:Fra-2-positive autoregulatory loop triggered by mitogen-activated protein kinase (MAPK) and Fra-2 phosphorylation sites by MAPK. 1035 14

Mitogen activated protein (MAP) kinase belongs to a large family of serine/threonine protein kinases, including extracellular-signal-regulated protein kinases (Erks), P38 kinase and c-Jun N-terminal kinases (JNKs). Although previous work has shown that both Erks and JNKs are activated in cells in response to ultraviolet (UV) irradiation, most studies have focused only on the role of JNKs in UV-induced AP-1 activation. Hence, the role of Erks in UV-induced AP-1 activity is not well defined. We here have investigated this issue by using MAP kinase kinase (MEK1) inhibitor PD098059 and a dominant negative Erk2, as well as wild-type Erk2, in a JB6 cell model. PD098059 inhibited UVB- or UVC-induced AP-1 activity and phosphorylation of MEK1 and Erks, but not JNKs, in JB6 Cl 41 cells. Overexpression of wild-type Erk2 in Cl 30.7b cells that contain small amounts of Erks caused a 46.6- or 138.1-fold increase of AP-1 activity by UVB and UVC, respectively; introduction of a dominant negative Erk2 into Cl 41 cells significantly blocked the UV-induced Erks activation as well as the AP-1 activation. In contrast, overexpression of wild-type Erk2 in Cl 30.7b cells and dominant negative Erk2 in Cl 41 cells did not show a marked influence on the phosphorylation of JNKs. These results demonstrate that activation of Erks, in addition to the previously reported JNKs, is required for UV-induced AP-1 activation.
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PMID:The extracellular-signal-regulated protein kinases (Erks) are required for UV-induced AP-1 activation in JB6 cells. 1036 53

The nuclear receptor mouse retinoid X receptor alpha (mRXRalpha) was shown to be constitutively phosphorylated in its NH2-terminal A/B region, which contains potential phosphorylation sites for proline-directed Ser/Thr kinases. Mutants for each putative site were generated and overexpressed in transfected COS-1 cells. Constitutively phosphorylated residues identified by tryptic phosphopeptide mapping included serine 22 located in the A1 region that is specific to the RXRalpha1 isoform. Overexpression and UV activation of the stress-activated kinases, c-Jun NH2-terminal kinases 1 and 2 (JNK1 and JNK2), hyperphosphorylated RXRalpha, resulting in a marked decrease in its electrophoretic mobility. This inducible hyperphosphorylation involved three residues (serines 61 and 75 and threonine 87) in the B region of RXRalpha and one residue (serine 265) in the ligand binding domain (E region). Binding assays performed in vitro with purified recombinant proteins demonstrated that JNKs did not interact with RXRalpha but bound to its heterodimeric partners, retinoic acid receptors alpha and gamma (RARalpha and RARgamma). Hyperphosphorylation by JNKs did not affect the transactivation properties of either RXRalpha homodimers or RXRalpha/RARalpha heterodimers in transfected cultured cells.
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PMID:Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases. 1038 91


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