Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Focal adhesion kinase-null (FAK(-/-) fibroblasts exhibit morphological and motility defects that are reversed by focal adhesion kinase (FAK) reexpression. The FAK-related kinase, proline-rich tyrosine kinase 2 (Pyk2), is expressed in FAK(-/-) cells, yet it exhibits a perinuclear distribution and does not functionally substitute for FAK. Chimeric Pyk2/FAK proteins were created and expressed in FAK(-/-) cells to determine the impact of Pyk2 localization to focal contacts. Whereas an FAK/Pyk2 COOH-terminal (CT) domain chimera was perinuclear distributed, stable expression of a Pyk2 chimera with the FAK-CT domain (Pyk2/FAK-CT) localized to focal contact sites and enhanced fibronectin (FN)-stimulated haptotactic cell migration equal to FAK-reconstituted cells. Disruption of paxillin binding to the FAK-CT domain (S-1034) inhibited Pyk2/FAK-CT localization to focal contacts and its capacity to promote cell motility. Paxillin binding to the FAK-CT was necessary but not sufficient to mediate the indirect association of FAK or Pyk2/FAK-CT with a beta 1-integrin-containing complex. Both FAK and Pyk2/FAK-CT but not Pyk2/FAK-CT S-1034 reconstituted FAK(-/-) cells, exhibit elevated FN-stimulated extracellular signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase (JNK) kinase activation. FN-stimulated FAK or Pyk2/FAK-CT activation enhanced both the extent and duration of FN-stimulated ERK2 activity which was necessary for cell motility. Transient overexpression of the FAK-CT but not FAK-CT S-1034 domain inhibited both FN-stimulated ERK2 and JNK activation as well as FN-stimulated motility of Pyk2/FAK-CT reconstituted cells. These gain-of-function studies show that the NH(2)-terminal and kinase domains of Pyk2 can functionally substitute for FAK in promoting FN-stimulated signaling and motility events when localized to beta-integrin-containing focal contact sites via interactions mediated by the FAK-CT domain.
 ...
PMID:Targeting Pyk2 to beta 1-integrin-containing focal contacts rescues fibronectin-stimulated signaling and haptotactic motility defects of focal adhesion kinase-null cells. 1114 24

A family of mitogen-activated protein (MAP) kinases comprising the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAP kinases are involved in proliferation and apoptosis. However, there are some arguments concerning the role of these kinases in Ag-induced B cell apoptosis. Two of the B lymphoma cell lines (CH31 and WEHI-231) susceptible to anti-IgM-induced apoptosis were used as a model. To address these issues, we examined the kinetics of anti-IgM-induced activation of MAP kinases and established cell lines overexpressing a dominant-negative (dn) mutant form of JNK1 (dnJNK1). Anti-IgM induced a sustained JNK1 activation with a peak at 8 h, with a marginal activation of ERK1/ERK2 in CH31 cells. The sustained JNK1 activation was not a secondary event through a caspase activation. The peak point of the JNK1 activation was just before the onset of a decline in mitochondrial membrane potential, which preceded anti-IgM-induced cell death. Following anti-IgM stimulation, dnJNK1 prevented a decline in mitochondrial membrane potential at 24 h, with a prolonged inhibition up to 72 h in WEHI-231, although it did so only partially during a later time period in CH31. The dnJNK1 cells also demonstrated diminished procaspase-3 activation and a decreased rate of apoptosis upon anti-IgM stimulation, with a concomitant increased arrest in G(1) phase, which could be explained by enhanced levels of cyclin-dependent kinase inhibitor p27(Kip1) protein. Thus, anti-IgM-induced JNK activation might be implicated in cell cycle progression as well as in apoptosis regulation, probably involving p27(Kip1) protein.
 ...
PMID:Prevention of anti-IgM-induced apoptosis accompanying G1 arrest in B lymphoma cells overexpressing dominant-negative mutant form of c-Jun N-terminal kinase 1. 1116 Feb 6

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.
 ...
PMID:Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. 1116 17

Mitogen-activated protein (MAP) kinases are important intracellular mediators for proliferation and hypertrophy and therefore may also regulate cardiomyoblast growth in hypertensive heart disease. Thus, the aim of the present study was to examine the activities of MAP kinases, namely extracellular signal-regulated kinase (ERK)1,2, c-Jun NH2-terminal kinases (JNK)1,2 and p38 MAP kinase, in myocardial tissue of 12-week-old Prague normotensive (PNR) and hypertensive rats (PHR), a model of genetic hypertension with marked cardiac hypertrophy. Systolic blood pressure was 121 +/- 5 in PNR and 208 +/- 15 mm Hg in PHR (p < 0.01). Total heart weight was 247 +/- 4 in PNR vs. 316 +/- 4 mg/100 g body weight in PHR (p < 0.01). Left and right ventricular weights were 121 +/- 5 and 53 +/- 3 in PNR vs. 168 +/- 4 (p < 0.01) and 57 +/- 2 mg/100 g body weight (n.s.) in PHR. Using anti-ERK2 Western blot analysis as well as immunocomplex ERK activity assay, we found no activation of ERK2 in left or right ventricular tissue of PHR and PNR. Similary, p38 MAP kinase phosphorylation and activity were not detectable. In contrast, Western blot analysis using antiphospho-JNK antibodies revealed in myocardial tissue of right and left ventricles significantly greater phosphorylation of JNK2 in PHR than in PNR. This finding was confirmed by immunocomplex JNK activity assay using ATF-2 as substrate, which demonstrated a significant increase in JNK activity in the left ventricle of PHR as compared to PNR (6.4 +/- 1.5 vs. 2.5 +/- 0.5 OD; each n = 5; p < 0.05). In conclusion, cardiac JNK2 seems to be regulated differently from ERK2 in this rat model. In PHR, as compared to PNR, we found enhanced activity of JNK2 in the left and right ventricles suggesting that JNK2 is involved in hypertensive cardiac disease. The rise in JNK in both ventricles may result indirectly from humoral stimuli, e.g., endothelin-1 and/or angiotensin II, and may contribute to ventricular hypertrophy in this model of spontaneous hypertension.
 ...
PMID:Cardiac hypertrophy in the Prague-hypertensive rat is associated with enhanced JNK2 but not ERK tissue activity. 1117 7

The role of p44/42 mitogen-activated protein kinase (MAPK), p38, and c-Jun NH(2)-terminal kinase (JNK) in tumor necrosis factor (TNF)-alpha-induced cyclooxygenase (COX)-2 expression was studied in NCI-H292 epithelial cells. TNF-alpha-mediated COX-2 expression and COX-2 promoter activity were inhibited by the MAPK kinase inhibitor PD98059 or the p38 inhibitor SB203580. Treatment of cells for 10 min with TNF-alpha resulted in activation of p44/42 MAPK, p38, and JNK. C2-ceramide (a cell-permeable ceramide analog), bacterial neutral sphingomyelinase (Smase; an enzyme that degrades sphingomyelin to ceramide), and N-oleoylethanolamine (a ceramidase inhibitor) all induced activation of MAPKs, COX-2 expression, nuclear factor (NF)-kappaB DNA-protein binding, and COX-2 promoter activity. The inactive analog, dihydro-C2-ceramide, had no effect. SMase- or C2-ceramide-induced COX-2 expression and COX-2 promoter activity were also inhibited by PD98059 or SB203580. Glutathione, a neutral SMase inhibitor, attenuated TNF-alpha- or SMase-induced activation of MAPKs, COX-2 expression, and COX-2 promoter activity. TNF-alpha- or C2-ceramide-induced COX-2 promoter activity was inhibited by the dominant negative mutant of extracellular signal-regulated kinase 2, p38, JNK, IkappaB kinase (IKK)1, or IKK2. IKK activity was stimulated by either TNF-alpha or C2-ceramide, and these effects were inhibited by PD98059 or SB203580. All these results suggest that, in NCI-H292 epithelial cells, activation of MAPKs by ceramide contributes to the TNF-alpha signaling that occurs downstream of neutral SMase activation and results in the stimulation of IKK1/2, and NF-kappaB in the COX-2 promoter, followed by initiation of COX-2 expression.
 ...
PMID:Tumor necrosis factor-alpha-induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogen-activated protein kinases, and IkappaB kinase 1/2 in human alveolar epithelial cells. 1117 44

We reported previously that the production of urokinase-type plasminogen activator receptor (uPAR) protein is greater in high-grade glioblastomas than in low-grade gliomas. Transcriptional activation of the uPAR gene or increased stability of the uPAR mRNA that encodes this protein could cause the increased production of this protein in cell lines of different grades of gliomas. We found similar half-life of uPAR mRNA of 10-12 h in glioblastoma multiforme (UWR3) and anaplastic astrocytoma (SW1783) cells. However, the human uPAR promoter was up-regulated 6-8-fold in SW1783 cells and 11-13-fold in UWR3 cells as compared with its activity in low-grade gliomas, a finding that correlates well with previous findings of increases in uPAR mRNA and protein levels in higher-grade gliomas. uPAR mRNA level was increased 11-fold over a 24-h period in low-grade glioma cell lines after treatment with phorbol myristate acetate. The region spanning -144 to -123 bp of the human uPAR promoter that contains the Sp-1 site and a PEA-3 element and an AP-1 site at -184 plays major roles in uPAR promoter activity in glioblastoma cells. Specific antibodies used in an electrophoretic mobility shift assay identified fra-1, fra-2, Jun D, and c-Jun proteins in the nuclear protein complex that bind a 51-mer containing the AP-1 consensus sequence at -184 and its flanking sequences in the uPAR promoter. We further studied the inhibition of uPAR promoter by coexpression of a transactivation domain lacking C-Jun; a dominant-negative ERK1 and ERK2 mutant and a dominant-negative C-raf in glioblastoma cell lines showed the repressed uPAR promoter activity compared with the effect of the empty expression vector. We conclude from our findings that increased transcription is the more likely mechanism underlying the increase in uPAR production in high-grade gliomas.
 ...
PMID:Regulation of the urokinase-type plasminogen activator receptor gene in different grades of human glioma cell lines. 1123 78

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.
 ...
PMID:Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. 1124 72

The expression of the P2 receptors and their functional responses were studied in rat thyroid FRTL-5 cells. RT-PCR analysis revealed transcripts for the G protein-coupled P2Y(2), P2Y(4) and P2Y(6) receptors, and for the transmitter-gated ion channel P2X(3), P2X(4) and P2X(5) subunits. In Fura-2-loaded cells, UTP, ATP, ATPgammaS or UDP increased [Ca(2+)](i), and behaved as potent full agonists, while 2-Methylthio-ATP (2-MeSATP), alpha,beta-methylene-ATP (alpha,beta-meATP) and pure ADP were weak agonists. The agonist-mediated [Ca(2+) ](i) increases were diminished in Ca(2+) -free buffer, and by pertussis toxin (PTX) or suramin treatments. ATP, UTP, UDP and ATPgammaS increased (3)H-thymidine incorporation into DNA and expression of the protooncogenes c-Fos and c-Jun, while 2-MeSATP was ineffective, and alpha,beta-meATP gave a response only at 100-microM dose. The ATP-stimulated expression of c-Fos and c-Jun was dependent on Ca(2+), and protein kinase C, but not on calmodulin or Ca(2+)/calmodulin-dependent protein kinase II. Extracellular signal-regulated kinases (ERK1 and ERK2) are also involved as the MEK inhibitor, PD98059, reduced both ATP-evoked (3)H-thymidine incorporation and c-Fos and c-Jun expression. These results indicate that multiple P2Y receptor subtypes and at least the P2X(5) subtype are functionally expressed in FRTL-5 cells, and that nucleotides acting via P2 receptors are involved in the regulation of DNA-synthesis.
 ...
PMID:Mechanisms of P2 receptor-evoked DNA synthesis in thyroid FRTL-5 cells. 1126 96

Mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1/CL100) is an inducible nuclear dual specificity protein phosphatase that can dephosphorylate and inactivate both mitogen- and stress-activated protein kinases in vitro and in vivo. However, the molecular mechanism responsible for the substrate selectivity of MKP-1 is unknown. In addition, it has been suggested that the signal transducers and activators of transcription 1 (STAT1) transcription factor is a physiological non-MAP kinase substrate for MKP-1. We have used the yeast two-hybrid assay to demonstrate that MKP-1 is able to interact selectively with the extracellular signal-regulated kinase 1/2 (ERK1/2), p38alpha, and c-Jun NH(2)-terminal kinase (JNK) MAP kinase isoforms. Furthermore, this binding is accompanied by catalytic activation of recombinant MKP-1 protein in vitro, and these end points show an absolute correlation with MKP-1 substrate selectivity in vivo. In contrast, MKP-1 does not interact with STAT1. Recombinant STAT1 does not cause catalytic activation of MKP-1; nor does MKP-1 block tyrosine phosphorylation of STAT1 in vivo. Both binding and catalytic activation of MKP-1 are abrogated by mutation of a conserved docking site in ERK2, p38alpha, and JNK1 MAP kinases. Within MKP-1, MAP kinase binding is mediated by the amino-terminal noncatalytic domain of the protein. However, mutation of a conserved cluster of positively charged residues within this domain abolishes the binding and activation of MKP-1 by ERK2 and p38alpha but not JNK1, indicating that there are distinct binding determinants for these MAP kinase isoforms. We conclude that the substrate selectivity of MKP-1 is determined by specific protein-protein interactions coupled with catalytic activation of the phosphatase and that these interactions are restricted to members of the MAP kinase family of enzymes.
 ...
PMID:Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1. 1127 99

The role of mitogen-activated protein kinase (MAPK) pathways as signal transduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-overload hypertrophy, we examined whether activation of MAPK pathways, namely, the extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic banding. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK-activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MAPK kinase cascades, particularly stress-activated MAPK and p38-MAPK and their target transcription factors c-Jun and ATF-2.
 ...
PMID:Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load. 1135 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>