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)

Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) activates the c-Jun NH2-terminal kinase (JNK) pathway, although no substrates for MEKK3 have been identified. We have examined the regulation by MEKK3 of MAPK kinase 7 (MKK7) and MKK6, two novel MAPK kinases specific for JNK and p38, respectively. Coexpression of MKK7 with MEKK3 in COS-7 cells enhanced MKK7 autophosphorylation and its ability to activate recombinant JNK1 in vitro. MKK6 autophosphorylation and in vitro activation of p38alpha were also observed following coexpression of MKK6 with MEKK3. MEKK2, a closely related homologue of MEKK3, also activated MKK7 and MKK6 in COS-7 cells. Importantly, immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7 and MKK6 in vitro. These data identify MEKK3 as a MAPK kinase kinase specific for MKK7 and MKK6 in the JNK and p38 pathways. We have also examined whether MEKK3 or MEKK2 activates p38 in intact cells using MAPK-activated protein kinase-2 (MAPKAPK2) as an affinity ligand and substrate. Anisomycin, sorbitol, or the expression of MEKK3 in HEK293 cells enhanced MAPKAPK2 phosphorylation, whereas MEKK2 was less effective. Furthermore, MAPKAPK2 phosphorylation induced by MEKK3 or cellular stress was abolished by the p38 inhibitor SB-203580, suggesting that MEKK3 is coupled to p38 activation in intact cells.
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PMID:MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. 1034 27

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

ERK1 and ERK2 associate with the tyrosine phosphatase PTP-SL through a kinase interaction motif (KIM) located in the juxtamembrane region of PTP-SL. A glutathione S-transferase (GST)-PTP-SL fusion protein containing the KIM associated with ERK1 and ERK2 as well as with p38/HOG, but not with the related JNK1 kinase or with protein kinase A or C. Accordingly, ERK2 showed in vitro substrate specificity to phosphorylate GST-PTP-SL in comparison with GST-c-Jun. Furthermore, tyrosine dephosphorylation of ERK2 by the PTP-SLDeltaKIM mutant was impaired. The in vitro association of ERK1/2 with GST-PTP-SL was highly stable; however, low concentrations of nucleotides partially dissociated the ERK1/2.PTP-SL complex. Partial deletions of the KIM abrogated the association of PTP-SL with ERK1/2, indicating that KIM integrity is required for interaction. Amino acid substitution analysis revealed that Arg and Leu residues within the KIM are essential for the interaction and suggested a regulatory role for Ser(231). Finally, coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention of ERK2 in the cytoplasm in a KIM-dependent manner. Our results demonstrate that the noncatalytic region of PTP-SL associates with mitogen-activated protein kinases with high affinity and specificity, providing a mechanism for substrate specificity, and suggest a role for PTP-SL in the regulation of mitogen-activated protein kinase translocation to the nucleus upon activation.
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PMID:Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. 1041 10

JEM-1 is a novel gene whose mRNA expression in acute promyelocytic leukemia (APL) is induced by retinoid treatments. The gene product, a 45 kDa basic nuclear factor containing a leucine repeat, was transiently expressed in HeLa or COS-7 cells and immunocharacterized within the nuclei in fine punctuated structures which increase in size after cell transfection. Jem-1 was not expressed in the nucleoli. Experimental deletion of peptide domains of Jem-1 (JemDelta331-400 and Jem DeltaL179-206) showed that its C-terminal sequence (Thr331 --> Leu400) is required for nuclear translocation, while the leucine repeat domain (Arg179 --> Glu206) has no influence on subcellular localization. The Jem-1 protein was not detected in the PML-containing nuclear bodies or in speckled structures containing the splicing factor SC-35. In contrast it was localized in the nucleus in structures containing activator protein-1 (AP-1). DNA mobility shift assays showed that the in vitro translated Jem protein interacts neither with the DNA binding site of AP-1, nor directly with in vitro co-translated c-Fos or/and c-Jun proteins bound to this specific sequence. Interestingly, Jem-1-1 increased substantially the transcriptional activity of c-Jun (three-fold) and more strongly that of ectopically co-expressed c-Fos and c-Jun (five- to six-fold), as measured by a CAT reporter gene driven by a heterologous promoter containing the AP-1 binding site of the human collagenase gene. These synergistic effects were strongly Jem-1 dose-dependent. However, Jem-1 alone showed no activity on the collagenase promoter. A deletion of the leucine repeat of Jem-1 (Arg179 --> Glu206) did not diminish the enhancer capacity of Jem-1 on AP-1 activity. In contrast, the enhanced AP-1 activity was abrogated when Jem-1 was deleted of its C-terminus (Thr331 --> Leu400). We conclude that the 45 kDa nuclear product of the JEM-1 gene has features of a novel transcription cofactor, which is enhancing AP-1 activity without directly interacting with c-Jun or c-Fos proteins. Possible implications of these findings for APL cell maturation are discussed.
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PMID:JEM-1, a novel nuclear co-factor: localisation and functional interaction with AP-1. 1060 19

Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has revealed a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary role for active ERKI/II in long-term potentiation in vivo. Using phospho-specific antibodies that recognize the activated form of ERKI/II, we find that the level of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activation of ERKI/II, without effect on the related kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase) in primary cortical cultures. ERKI/II activation is Src-dependent and partially phosphoinositide-3 kinase- and Ca(2+)-dependent but is PKC-independent. M1-M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal transduction pathway similar to that operating in neurons. The nature of the signal transduction suggests that ERKI/II can serve as a convergence site for mAChR activation and other neurotransmitter receptors.
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PMID:ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. 1064 2

The by-product of lipid peroxidation, 4-hydroxynonenal (HNE), was shown to cause apoptosis in PC12 cells. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in these cells. Specifically, we determined the effect of HNE on the activities of mitogen-activated protein (MAP) kinases involved in early signal transduction. Within 15 to 30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before it returned to control level at 1 h post-treatment. In contrast, activities of extracellular signal-regulated kinase and p38 MAP kinase remained unchanged from their baseline levels. Stress-activated protein kinase kinase (SEK1), an upstream kinase of JNK, was also activated within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 and apoptosis signal-regulating kinase 1 (ASK1), an upstream kinase of SEK1, was demonstrated by the transient transfection of cDNA for wild-type SEK1 or ASK1 together with JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when either of the dominant negative mutant of SEK1 or ASK1 was cotransfected with JNK. Pretreatment of PC12 cells with a survival-promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, neither caused apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p38 MAP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the selective JNK activation by HNE is critical for the apoptosis of PC12 cells and that the HNE-mediated apoptosis is likely to be mediated through the activation of the ASK1-SEK1-JNK pathway without activation of extracellular signal-regulated kinase or p38 MAP kinase.
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PMID:Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells. 1095 46

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL(1)) receptor. It has been shown that activation of ORL(1) receptor leads to inhibition of the adenylyl cyclase activity, but stimulation of the extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases. In this report, we demonstrate that activation of the G protein-coupled ORL(1) receptor in transfected COS-7 cells leads to stimulation of the JNK subgroup of mitogen-activated protein kinases in a Ras/Rac-dependent manner, and it was insensitive to wortmannin. This increased JNK activity was mainly mediated by PTX-sensitive G(i) proteins, and partially contributed by a PTX-insensitive component. Among all known PTX-insensitive G proteins, G(z), G(12), G(14), and G(16) seemed to have functional coupling with the ORL(1) receptor in terms of JNK activation. Stimulation of the endogenous ORL(1) receptor in NG108-15 cells also led to activation of a PTX-sensitive JNK activity in a wortmannin-insensitive manner. The induced JNK activation is accompanied by the active phosphorylation of c-Jun and activating transcription factor-2. This is the first report that demonstrates the stimulatory effect of ORL(1) receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.
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PMID:Regulation of c-Jun N-terminal kinase by the ORL(1) receptor through multiple G proteins. 1108 45

beta-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of beta-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase 1 (ASK1) and mitogen-activated protein kinase (MAPK) kinase 4 were also found in complex with beta-arrestin 2. Cellular transfection of beta-arrestin 2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of beta-arrestin 2 and active JNK3 to intracellular vesicles. Thus, beta-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR.
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PMID:Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. 1118 9

GnRH has been showed to regulate hCG expression and secretion from the placenta through a GnRH receptor (GnRHR)-mediated process. Recently, we have reported the isolation of human GnRHR full-length complementary DNA from the human placental cells including choriocarcinoma JEG-3 cells, immortalized extravillous trophoblasts, and primary cultures of trophoblasts. Despite these observations, the molecular mechanism that controls the transcription regulation of the GnRHR gene expression in the placenta remains unknown. Here we described the identification of an upstream placenta-specific promoter located between nucleotide (nt) -1737 and -1346 (relative to the translation start site) for the human GnRHR gene. Using transient transfection studies, this upstream promoter has been shown to determine the placental cell-specific expression of this gene. Primer extension studies further confirmed the utilization of this promoter in JEG-3 cells in vivo. By mutagenesis coupled to functional studies, we have identified four putative transcription factor-binding sites, namely human glucocorticoid receptor (hGR)-Oct-1 (nt -1718 to -1710), hGR-cAMP response element (CRE; nt -1649 to -1641), hGR-GATA (nt -1602 to -1597), and hGR-activating protein-1 (nt -1518 to -1511), that are essential to the expression of this gene. Mutations of these cis-acting motifs reduced the promoter activity. The CRE and GATA motifs were subsequently shown to be placenta specific, as mutations of these motifs caused a dramatic loss in promoter activities in the placental JEG-3 cells, but not in the ovarian carcinoma OVCAR-3, monkey kidney COS-1, and human embryonic kidney 293 cells. Gel mobility assays confirmed the binding of nuclear proteins Oct-1, CRE-binding protein, GATA-2, GATA-3, c-Fos, and c-Jun from JEG-3 cells to these four elements.
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PMID:Functional mapping of a placenta-specific upstream promoter for human gonadotropin-releasing hormone receptor gene. 1125 Sep 31

Cytotoxic lipid peroxides such as 4-hydroxy-2-nonenal (HNE) are produced when cells are exposed to toxic chemicals. However, the mechanism by which HNE induces cell death has been poorly understood. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in PC12 cells by measuring the activities of the mitogen-activated protein (MAP) kinases involved in early signal transduction pathways. Within 15-30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before returning to control level after 1 h post-treatment. In contrast, activities of extracellular signal regulated kinase (ERK) and p38 MAP kinase remained unchanged from their basal levels. SEK1, an upstream kinase of JNK, was also activated (phosphorylated) within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 was demonstrated by the transient transfection of cDNA for wild type SEK1 and JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when the dominant negative mutant of SEK1 was co-transfected with JNK. Pretreatment of PC12 cells with a survival promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, caused neither apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p38 MAP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the HNE-mediated apoptosis of PC12 cells is likely to be mediated through the selective activation of the SEK1-JNK pathway without activation of ERK or p38 MAP kinase.
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PMID:Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-terminal protein kinase pathway. 1130 8


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