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 amino-terminal kinase (JNK) is a member of the stress-activated group of mitogen-activated protein (MAP) kinases that are implicated in the control of cell growth. A murine cytoplasmic protein that binds specifically to JNK [the JNK interacting protein-1 (JIP-1)] was characterized and cloned. JIP-1 caused cytoplasmic retention of JNK and inhibition of JNK-regulated gene expression. In addition, JIP-1 suppressed the effects of the JNK signaling pathway on cellular proliferation, including transformation by the Bcr-Abl oncogene. This analysis identifies JIP-1 as a specific inhibitor of the JNK signal transduction pathway and establishes protein targeting as a mechanism that regulates signaling by stress-activated MAP kinases.
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PMID:A cytoplasmic inhibitor of the JNK signal transduction pathway. 923 93

Animals exposed to kainic acid (KA) induced status epilepticus display a striking pattern of selective neuronal vulnerability in the hippocampus. Neurons in the hilus/CA3 and CA1 subfields appear particularly sensitive whereas dentate gyrus (DG) granule cells are resistant. The molecular basis for this differential susceptibility remains largely unknown. Recently, an involvement of nitric oxide, c-Jun amino-terminal kinases (JNK) and interleukin-1 beta converting enzyme (ICE)-related proteases has been proposed in KA induced neuronal cell death. In the present study, we have determined the regional expression of transcripts for two modulating genes operating in these pathways, i.e., the endogenous protein inhibitor of neuronal nitric oxide synthase (PIN), and a cytoplasmic inhibitor of the JNK signal transduction pathway, designated JNK interacting protein-1 (JIP-1) and of the gene for the apoptosis-executing protease Caspase-3 in KA-treated animals. The expression of PIN and JIP-1 was found significantly upregulated in granule cells of the resistant DG. In contrast, an induction of the ICE-related protease Caspase-3 was observed in vulnerable hippocampal regions, i.e. CA1, CA3 and hilus. These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model.
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PMID:Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. 1010 Dec 44

Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c-Jun has been shown in various cell death paradigms. Inhibition of the JNK signal transduction pathway prevented neuronal cell death both in vitro and in vivo. In the present study, nuclear phospho-c-Jun immunoreactivity became apparent selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by immunoblot analysis of hippocampal extracts. Expression of JNK interacting protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post-ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons. Our data suggest that transcription factors p53 and phospho-c-Jun may contribute to programmed CA1 cell death following ischemia.
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PMID:Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in hippocampal CA1 neurons following global ischemia. 1058 7

To study the role of MAPK cascades in the regulation of naturally occurring human immunodeficiency virus type 1 long terminal repeats (HIV-1 LTRs), we analyzed several HIV-1 LTRs from patients at different stages of disease progression. One of these naturally occurring HIV-1 LTRs contains an insertion termed the most frequent naturally occurring length polymorphism (MFNLP) and exhibited high inducibility upon T cell activation. We found that the protein kinase mixed lineage kinase 3/src-homology 3 domain-containing proline-rich kinase, a specific activator of the stress-activated protein kinase (SAPK)/JNK signaling pathway in T lymphocytes, induces high transcriptional activation of this promoter. Promoter inducibility is inhibited by the SAPK/JNK inhibitor, the JNK binding domain of the JNK interacting protein 1, and Tam-67 (N-terminal deletion mutant of c-Jun). In electrophoretic mobility shift assay, several protein complexes were found to bind to the MFNLP sequence in T cells. We identified AP-1 factors c-Fos and JunB as MFNLP-binding proteins, whose binding is abolished by introducing point mutations in the 3'-half of the MFNLP sequence. Introduction of these point mutations into the MFNLP containing HIV-1 LTR reduced src-homology 3 domain-containing proline-rich kinase -mediated transactivation. These data indicate that the AP-1-like binding site in the MFNLP sequence gives rise to a higher inducibility of natural HIV-LTRs by the SAPK/JNK signaling pathway.
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PMID:Transactivation of naturally occurring HIV-1 long terminal repeats by the JNK signaling pathway. The most frequent naturally occurring length polymorphism sequence introduces a novel binding site for AP-1 factors. 1076 60

c-Jun response is involved in the development of ischemic brain injury, which is activated by c-Jun N-terminal kinase-1 (JNK-1). The activity of JNK-1 is strictly regulated, and only the phosphorylated form of JNK (phospho-JNK) which is translocated to the nucleus has an ability to activate c-Jun response. There is a protein which inhibits JNK-1 activation, and known as JNK interacting protein-1 (JIP-1). In this study, we investigated change in JNK-1, phospho-JNK, and JIP-1 immunoreactivity in rat brain after transient middle cerebral artery (MCA) occlusion. Immunoreactive JNK-1 was scant in the sham-control brain, but it was induced at 1 h after reperfusion, which was slightly increased at 3 h of reperfusion. By contrast, phospho-JNK remained negative till 3 h. At 8 h, JNK-1 and phospho-JNK became distinctly positive, and nuclei as well as cytoplasm were stained. Thereafter, immunoreactivity for JNK-1 and phospho-JNK became furthermore dense, and most neurons revealed positively stained nuclei. Immunoreactivity for JIP-1 remained negative till 8 h of reperfusion, but at 24 and 72 h, cytoplasm of cortical neurons at the MCA boundary area was positively stained. This JIP-1 induction got behind the JNK-1 activation, and therefore, may be a vain effort for neurons to survive. Inhibition of JNK-1 activation might become an innovative means of therapy for stroke treatment in the future.
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PMID:c-Jun N-terminal kinase (JNK) and JNK interacting protein response in rat brain after transient middle cerebral artery occlusion. 1077 32

c-Jun N-terminal kinases (JNKs) regulate gene expression by phosphorylating transcription factors, such as c-Jun. Studies with JNK: knockout mice suggest that JNK activity may be required for excitotoxin-induced apoptosis in the adult hippocampus and for apoptosis in the developing embryonic neural tube. Here we investigate the role of JNKs in classical neurotrophin-regulated developmental neuronal death by using nerve growth factor (NGF)-dependent sympathetic neurones. In this system, NGF withdrawal leads to an increase in JNK activity, an increase in c-Jun protein levels and c-Jun N-terminal phosphorylation before the cell death commitment point, and c-Jun activity is required for cell death. To inhibit JNK activity in sympathetic neurones we have used two different JNK inhibitors that act by distinct mechanisms: the compound SB 203580 and the JNK binding domain (JBD) of JNK interacting protein 1 (JIP-1). We demonstrate that JNK activity is required for c-Jun phosphorylation, c-jun promoter activation and NGF withdrawal-induced apoptosis. We also show that ATF-2, a c-Jun dimerization partner that can regulate c-jun gene expression, is activated following NGF deprivation. Finally, by co-expressing the JBD and a regulatable c-Jun dominant negative mutant we demonstrate that JNK and AP-1 function in the same pro-apoptotic signalling pathway after NGF withdrawal.
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PMID:Direct inhibition of c-Jun N-terminal kinase in sympathetic neurones prevents c-jun promoter activation and NGF withdrawal-induced death. 1123 29

Extracellular signals are transduced into cells through mitogen-activated protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a protein, JLP (c-Jun NH2-terminal kinase-associated leucine zipper protein), which acts as a scaffolding protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
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PMID:JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. 1239 7

12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway.
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PMID:JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA). 1513 88

A sequential kinase cascade culminating in activation of c-Jun N-terminal kinases (JNKs) plays a fundamental role in promoting apoptotic death in many cellular contexts. The mechanisms by which this pathway is engaged in response to apoptotic stimuli and suppressed in viable cells are largely unknown. Here, we show that apoptotic stimuli increase endogenous cellular levels of pathway components, including POSH, mixed lineage kinases (MLKs), and JNK interacting protein 1, and that this effect occurs through protein stabilization and requires the presence of POSH as well as activation of MLKs and JNKs. Our findings suggest a self-amplifying, feed-forward loop mechanism by which apoptotic stimuli promote the stabilization of JNK pathway components, thereby contributing to cell death.
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PMID:Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop. 1626 Jun 9

Acute ethanol loading causes oxidative stress to activate cell-death signaling via c-Jun NH2-terminal kinase (JNK) in livers. JNK are stimulated under conditions of endoplasmic reticulum (ER) stress which causes programmed cell death. However, no remarked cell death was observed in acute ethanol intoxication. Akt, one of the cell survival protein kinases, may be activated under ethanol loading. The aim of this study was to estimate activation of JNK and ER stress, role of ethanol metabolism on the activation, and association of JNK with Akt under acute ethanol loading using the perfused rat liver system. Activation of JNK or Akt and association of JNK and Akt with JNK interacting protein 1 were estimated by immunoprecipitation and immunoblotting. Expression of 78 kDa glucose-regulated protein (GRP78) mRNA, a biomarker of ER stress, was detected by quantitative real-time RT-PCR. Activations of JNK and Akt were enhanced by co-treatment with ethanol and a classical inhibitor of alcohol dehydrogenase (ADH). Addition of an antioxidant reduced the activation of JNK. Ethanol loading with ADH inhibition causes down-regulation of GRP78 mRNA levels. Therefore, these findings suggest first revelation that inhibition of ethanol metabolism complicates oxidative and ER stresses produced by ethanol.
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PMID:Ethanol rapidly causes activation of JNK associated with ER stress under inhibition of ADH. 1634 92


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