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)

In GN4 rat liver epithelial cells, angiotensin II (Ang II) and other agonists which activate phospholipase C stimulate tyrosine kinase activity in a calcium-dependent, protein kinase C (PKC)-independent manner. Since Ang II also produces a proliferative response in these cells, we investigated downstream signaling elements traditionally linked to growth control by tyrosine kinases. First, Ang II, like epidermal growth factor (EGF), stimulated AP-1 binding activity in a PKC-independent manner. Because increases in AP-1 can reflect induction of c-Jun and c-Fos, we examined the activity of the mitogen-activated protein (MAP) kinase family members Erk-1 and -2 and the c-Jun N-terminal kinase (JNK), which are known to influence c-Jun and c-Fos transcription. Ang II stimulated MAP kinase (MAPK) activity but only approximately 50% as effectively as EGF; again, these effects were independent of PKC. Ang II also produced a 50- to 200-fold activation of JNK in a PKC-independent manner. Unlike its smaller effect on MAPK, Ang II was approximately four- to sixfold more potent in activating JNK than EGF was. Although others had reported a lack of calcium ionophore-stimulated JNK activity in lymphocytes and several other cell lines, we examined the role of calcium in GN4 cells. The following results suggest that JNK activation in rat liver epithelial cells is at least partially Ca(2+) dependent: (i) norepinephrine and vasopressin hormones that increase inositol 1,4,5-triphosphate stimulated JNK; (ii) both thapsigargin, a compound that produces an intracellular Ca(2+) signal, and Ca(2+) ionophores stimulated a dramatic increase in JNK activity (up to 200-fold); (iii) extracellular Ca(2+) chelation with ethylene glycol tetraacetic acid (EGTA) inhibited JNK activation by ionophore and intracellular chelation with 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl-ester (BAPTA-AM) partially inhibited JNK activation by Ang II or thapsigargin; and (iv) JNK activation by Ang II was inhibited by pretreatment of cells with thapsigargin and EGTA, a procedure which depletes intracellular Ca(2+) stores. JNK activation following Ang II stimulation did not involve calmodulin; either W-7 nor calmidizolium, in concentrations sufficient to inhibit Ca(2+)/calmodulin-dependent kinase II, blocked JNK activation by Ang II. In contrast, genistein, in concentrations sufficient to inhibit Ca(2+)-dependent tyrosine phosphorylation, prevented Ang II and thapsigargin-induced JNK activation. In summary, in GN4 rat liver epithelial cells, Ang II stimulates JNK via a novel Ca(2+)-dependent pathway. The inhibition by genistein suggest that Ca(2+)-dependent tyrosine phosphorylation may modulate the JNK pathway in a cell type-specific manner, particularly in cells with a readily detectable Ca(2+)-regulated tyrosine kinase.
 ...
PMID:Angiotensin II stimulates calcium-dependent activation of c-Jun N-terminal kinase. 756 68

1. The human endothelin-1 (ET-1) gene, which is located on chromosome 6, contains cis-regulatory elements in the 5'-flanking region including the TPA-responsive element, nuclear factor 1 binding element and GATA motif. 2. The expression of preproendothelin-1 (PPET-1) mRNA is regulated by a mechanism involving receptor mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells. 3. Activation of protein kinase C results in the synthesis of c-Jun protein and the rapid dephosphorylation of c-Jun protein. Consequently, the binding activity of c-Jun protein to the TPA-responsive element increases, and this causes the induction of PPET-1 mRNA. 4. The microtubular system seems to play some important roles in ET-1 secretion, especially in the process of transferring the synthesized ET-1 to the cell surface of the endothelial cells. 5. The secretion of ET-1 from endothelial cells is also regulated by intracellular Ca2+ released from the Ca2+ store and by Ca2+-calmodulin complex. The phosphorylation of the myosin light chain, elicited by myosin light chain kinase and activated by Ca2+-calmodulin complex, facilitates the formation of filamentous myosin and actin which probably participate in ET-1 secretion especially in transporting the ET-1-containing vesicles towards the cell membrane in the stimulated endothelial cells. 6. Many cultured cells, other than endothelial cells, also secret ET-1 into the culture medium and this secretion can be stimulated by a variety of agents.
 ...
PMID:The control of endothelin-1 secretion. 787 27

Two cis-acting elements GM-kappa B/GC-box and CLE0, of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene are required for maximal induction in Jurkat T cells by costimulation with phorbol-12-myristate acetate (PMA) and Ca2+ ionophore (A23187). The GM-kappa B sequence is recognized by NF-kappa B, which is mainly induced by PMA. The CLE0 sequence interacts with factors, related to a PMA-induced AP-1 and a PMA/A23187-induced NF-AT. We examined whether signal transducing components in T cells can activate transcription of the GM-CSF gene. Cotransfection of NF-kappa B (p50/p65)- or AP-1 (c-Jun/c-Fos)-expression vectors into Jurkat cells with a luciferase reporter containing the GM-CSF promoter did not stimulate transcription from the GM-CSF promoter. In contrast, cotransfection with a combination of NF-kappa B and AP-1 significantly augmented transcription from the GM-CSF promoter containing the GM-kappa B/GC-box and the CLE0 (AP-1/NF-AT). Expression of a constitutively active calcineurin (CN), a Ca2+/calmodulin-dependent protein phosphatase, potentiated by two fold the transcriptional activation by NF-kappa B/AP-1. Both constitutively active forms of CN and protein kinase C (PKC) synergistically activated transcription from the GM-CSF promoter. These results suggest that cooperation among NF-kappa B-, AP-1- and NF-AT-binding sequences is required for induction of the GM-CSF gene through PKC- and Ca2+-signaling pathways downstream of T cell activation.
 ...
PMID:Calcineurin activates transcription from the GM-CSF promoter in synergy with either protein kinase C or NF-kappa B/AP-1 in T cells. 813 80

Membrane depolarization of NG108 cells gives rapid (< 5 min) activation of Ca2+/calmodulin-dependent protein kinase IV (CaM-KIV), as well as activation of c-Jun N-terminal kinase (JNK). To investigate whether the Ca2+-dependent activation of mitogen-activated protein kinases (ERK, JNK, and p38) might be mediated by the CaM kinase cascade, we have transfected PC12 cells, which lack CaM-KIV, with constitutively active mutants of CaM kinase kinase and/or CaM-KIV (CaM-KKc and CaM-KIVc, respectively). In the absence of depolarization, CaM-KKc transfection had no effect on Elk-dependent transcription of a luciferase reporter gene, whereas CaM-KIVc alone or in combination with CaM-KKc gave 7- to 10-fold and 60- to 80-fold stimulations, respectively, which were blocked by mitogen-activated protein (MAP) kinase phosphatase cotransfection. When epitope-tagged constructs of MAP kinases were co-transfected with CaM-KKc plus CaM-KIVc, the immunoprecipitated MAP kinases were activated 2-fold (ERK-2) and 7- to 10-fold (JNK-1 and p38). The JNK and p38 pathways were further investigated using specific c-Jun or ATF2-dependent transcriptional assays. We found that c-Jun/ATF2-dependent transcriptions were enhanced 7- to 10-fold by CaM-KIVc and 20- to 30-fold by CaM-KKc plus CaM-KIVc. In the case of the Jun-dependent transcription, this effect was not due to direct phosphorylation of c-Jun by activated CaM-KIV, since transcription was blocked by a dominant-negative JNK and by two MAP kinase phosphatases. Mutation of the phosphorylation site (Thr196) in CaM-KIV, which mediates its activation by CaM-KIV kinase, prevented activation of Elk-1, c-Jun, and ATF2 by the CaM kinase cascade. These results establish a new Ca2+-dependent mechanism for regulating MAP kinase pathways and resultant transcription.
 ...
PMID:Regulation of mitogen-activated protein kinases by a calcium/calmodulin-dependent protein kinase cascade. 885 61

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.
 ...
PMID:Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element. 921 60

c-Fos/c-Jun dimers (activating protein-1 transcription factor) are involved in the modulatory actions of angiotensin II (Ang II) on brain norepinephrine neurons, effects mediated via Ang II type 1 (AT1) receptors. The transcriptional activities of c-Fos and c-Jun can be augmented by Fos-regulating kinase (FRK) and c-Jun NH2-terminal kinase (JNK), respectively. In this study, we investigated the effects of Ang II on FRK and JNK activities in neurons cultured from newborn rat hypothalamus and brain stem, which include a population of catecholaminergic cells containing AT1 receptors. Ang II caused time-dependent increases in the activation of FRK and JNK, effects completely inhibited by the AT1 receptor antagonist losartan but not by the Ang II type 2 (AT2) receptor blocker PD123,319. The stimulation of FRK activity by Ang II was abolished by the protein kinase C (PKC) inhibitor GF109203X or the calcium chelator BAPTA, but not by inhibition of calmodulin or calcium/calmodulin-dependent protein kinase II. However, the activation of JNK by Ang II was not dependent on PKC or another calcium-dependent mechanism. These data demonstrate that Ang II stimulates activation of FRK and JNK in neuronal cells, actions that may contribute to the neuromodulatory effects of this peptide.
 ...
PMID:Angiotensin II stimulates activation of Fos-regulating kinase and c-Jun NH2-terminal kinase in neuronal cultures from rat brain. 942 21

Calcium is the principal second messenger in the control of gene expression by electrical activity in neurons. Recruitment of the coactivator CREB-binding protein, CBP, by the prototypical calcium-responsive transcription factor, CREB and stimulation of CBP activity by nuclear calcium signals is one mechanism through which calcium influx into excitable cells activates gene expression. Here we show that another CBP-interacting transcription factor, c-Jun, can mediate transcriptional activation upon activation of L-type voltage-gated calcium channels. Calcium-activated transcription mediated by c-Jun functions in the absence of stimulation of the c-Jun N-terminal protein kinase (JNK/SAPK1) signalling pathway and does not require c-Jun amino acid residues Ser63 and Ser73, the two major phosphorylation sites that regulate c-Jun activity in response to stress signals. Similar to CREB-mediated transcription, activation of c-Jun-mediated transcription by calcium signals requires calcium/ calmodulin-dependent protein kinases and is dependent on CBP function. These results identify c-Jun as a calcium-regulated transcriptional activator and suggest that control of coactivator function (i.e. recruitment of CBP and stimulation of CBP activity) is a general mechanism for gene regulation by calcium signals.
 ...
PMID:c-Jun functions as a calcium-regulated transcriptional activator in the absence of JNK/SAPK1 activation. 1006 99

Reactive oxygen species (ROS) are implicated in the pathogenesis of several proliferative diseases, including atherosclerosis and cancer. Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in cell proliferation and differentiation. To gain insight into molecular mechanisms by which ROS influence the pathogenesis of these diseases, I have studied the effect of H(2)O(2), a ROS, on eIF4E phosphorylation. H(2)O(2) induced eIF4E phosphorylation in a dose- and time-dependent manner in growth-arrested smooth muscle cells (SMC). H(2)O(2)-induced eIF4E phosphorylation occurred on serine residues. PD098059, a specific inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase inhibited ERK activities but had no significant effect on eIF4E phosphorylation induced by H(2)O(2). Similarly, SB203580, a specific inhibitor of p38 MAPK, although inhibiting H(2)O(2)-induced p38 MAPK activity, had no effect on H(2)O(2)-induced eIF4E phosphorylation. Calphostin C, a specific inhibitor of protein kinase C, also had no effect on H(2)O(2)-induced eIF4E phosphorylation. In contrast, trifluoperazine, an antagonist of calcium/calmodulin kinases, completely blocked H(2)O(2)-induced eIF4E phosphorylation. In addition, intracellular and extracellular Ca(2+) chelators significantly inhibited H(2)O(2)-induced eIF4E phosphorylation. Despite its ability to induce eIF4E phosphorylation, H(2)O(2) had no significant effect on protein levels and new protein synthesis as compared with control. In contrast, it induced the expression of c-Fos, c-Jun, and HSP70 in a time-dependent manner in SMC. Together, these results suggest that H(2)O(2), a ROS and a cellular oxidant, induces eIF4E phosphorylation in a manner that is dependent on Ca(2+) and Ca(2+)/calmodulin kinases and independent of ERKs, p38 MAPK, and protein kinase C. These results also suggest that enhanced eIF4E phosphorylation by H(2)O(2) appears to be an important event in SMC in response to oxidant stress and that eIF4E phosphorylation may be associated with the translation of a small subset of mRNAs such as c-fos, c-jun, and HSP70 gene mRNAs, whose products may have a critical role in cell survival.
 ...
PMID:Oxidant stress stimulates phosphorylation of eIF4E without an effect on global protein synthesis in smooth muscle cells. Lack of evidence for a role of H202 in angiotensin II-induced hypertrophy. 1082 72

Secalonic acid D (SAD), a mycotoxin produced by Penicillium oxalicum in corn, induces cleft palate (CP) in the offspring of exposed dams. Results of recent studies suggest that protein kinase C (PKC) inhibition by SAD may be relevant to its CP-induction. Downstream effects of PKC are determined by the nature of transcription factors (TF) that form the activator protein-1 (AP-1) and the binding of AP-1 (and other TF) to the phorbol 12-O-tetradecanoate-13 acetate-response element (TRE) to form AP-1-TRE complex, neither of which have been studied in the palate. The aims of the present study were to identify the components of the murine palatal AP-1-TRE complex during development and to uncover the effects of SAD on this complex. Western blots and gel mobility shift assays of control palatal nuclear extracts revealed that, although all relevant TF are present in the palate throughout development, only cyclic-AMP response element (CRE) binding protein (CREB) and CRE-modulator protein-1 (CREM-1) and activating transcription factor-1 bound to TRE on Gestation Day (GD) 12. The pattern shifted to c-Jun and c-Fos (known AP-1 components) on GD 13 and 14. In SAD-treated offspring, however, CREM-1 alone; c-Jun, c-Fos, and CREB; and c-Jun and c-Fos bound to TRE on GD 12, 13, and 14, respectively. Binding of TF to TRE was inhibited by SAD on both GD 12 and 13. These results suggest that a dynamic shift in the binding of TF to TRE from PKA- to PKC-responsive TF occurs during palate development and that teratogens such as SAD can alter both the nature and extent of TF binding to TRE.
 ...
PMID:Secalonic acid D alters the nature of and inhibits the binding of the transcription factors to the phorbol 12-O-tetradecanoate-13 acetate-response element in the developing murine secondary palate. 1109 66

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


1 2 3 4 5 Next >>