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)

Exposure of mammalian cells to ultraviolet (UV) light or glucose deprivation activates c-Jun NH2-terminal protein kinase (JNK). However, the exact mechanism by which UV induces JNK activation is not yet understood completely. Previously, we have observed that glucose deprivation activates the ASK1-SEK1-JNK signal transduction pathway. In the present study, we reveal that UVC irradiation-induced JNK activation has a different signal transduction pathway from glucose deprivation. UVC irradiation increases the interaction between JIP3 and MEKK1, SEK1, while glucose deprivation increases the interaction between JIP3 and ASK1, SEK1, and JNK. UVC irradiation activates MEKK1 rather than ASK1. We also observed that MEKK1 interacted with Grb2 and Grb2-MEKK1 complex was recruited to epidermal growth factor receptor (EGFR) after UVC irradiation. Taken together, our data demonstrate that UVC-induced JNK activation adopts a different signaling cascade (EGFR-Grb2-MEKK1-SEK1-JNK) from glucose deprivation (ASK1-SEK1-JNK).
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PMID:Differential activation of the JNK signal pathway by UV irradiation and glucose deprivation. 1702 35

The impact of human chorionic gonadotropin (hCG) on prostate carcinoma viability was investigated. Treatment of LNCaP and PC-3 cells with hCG modestly reduced cell viability within 96 h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of epidermal growth factor receptor (ERBB1) via a Galpha(i)-, mitogen-activated protein kinase kinase (MEK)1/2-, and metalloprotease-dependent paracrine mechanism, effects that were further enhanced after radiation exposure, and that were causal in prolonged intense activation of poly(ADP-ribose) polymerase (PARP). Inhibition of ERBB1, MEK1, or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon c-Jun NH2-terminal kinase 1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression. Inhibition of phosphatidylinositol 3-kinase, expression of dominant-negative AKT, or treatment with the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The enhancing effect of lovastatin was reproduced by incubation with a geranylgeranyl transferase inhibitor and blocked by coexposure to geranylgeranyl pyrophosphate. Treatment with hCG and lovastatin decreased expression of BCL-(XL) and XIAP, and increased expression of IkappaB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IkappaB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-(XL) levels in cells expressing dominant-negative IkappaB. The promotion of hCG lethality by lovastatin was abolished by overexpression of BCL-(XL), and was dependent upon activation of caspase-9. Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells.
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PMID:Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment. 2741 95

We have previously reported that platelet-activating factor (PAF) is present in very high levels in the ovine fetal lung and circulation and that PAF serves as an important physiological vasoconstrictor of the pulmonary circulation in utero. However, it is not known whether PAF stimulates pulmonary vascular smooth muscle cell (SMC) proliferation. In this study, we used ovine fetal pulmonary venous SMCs as our model system to study the effects and mechanisms of action of PAF on SMC proliferation. We found that PAF induced SMC proliferation in a dose-dependent manner. PAF also stimulated activation of both ERK and p38 but not c-Jun NH(2) terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. PAF (10 nM) induced phosphorylation of epidermal growth factor receptor (EGFR). Specific inhibition of EGFR by AG-1478 and by the expression of a dominant-negative EGFR mutant in SMCs attenuated PAF-stimulated cell proliferation. Inhibition of heparin-binding EGF-like growth factor (HB-EGF) release by CRM-197 and inhibition of matrix metalloproteinases (MMP) by GM-6001 abolished PAF-induced MAP kinase activation and cell proliferation. Increased alkaline phosphatase (AP) activity after PAF treatment in AP-HB-EGF fusion construct-transfected SMCs indicated that PAF induced the release of HB-EGF within 1 min. Gelatin zymography data showed that PAF stimulated MMP-2 activity and MMP-9 activity within 1 min. These results suggest that PAF promotes pulmonary vascular SMC proliferation via transactivation of EGFR through MMP activation and HB-EGF, resulting in p38 and ERK activation and that EGFR transactivation is essential for the mitogenic effect of PAF in pulmonary venous SMC.
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PMID:Platelet-activating factor induces ovine fetal pulmonary venous smooth muscle cell proliferation: role of epidermal growth factor receptor transactivation. 1732 18

Aplidin (plitidepsin) is a novel anticancer drug isolated from the marine tunicate Aplidium albicans. Aplidin shows potent antitumor activity in preclinical models against a wide variety of human tumors. Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies. Moreover, clinical studies of Aplidin in combination with other agents are ongoing because it generally lacks cross-resistance with other known cytotoxic drugs. The mode of action of Aplidin in tumor cells is only partially understood. Aplidin induces an early oxidative stress response, which results in a rapid and sustained activation of the epidermal growth factor receptor, the nonreceptor protein tyrosine kinase Src, and the serine threonine kinases c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase. Here, we show that sensitivity to Aplidin correlates inversely with the levels of expression of the cyclin-dependent kinase inhibitor p27(kip1) (p27) in a panel of low passaged human sarcoma cell lines. Aplidin induces p27 through an oxidation-dependent mechanism and the reduction of p27 levels by specific short hairpin RNA increases Aplidin sensitivity. We confirmed these results in p27 null mouse embryonic fibroblasts corroborating the specificity of the p27 role in Aplidin response because p21(waf1) null mouse embryonic fibroblasts do not show this increased sensitivity. We propose a mechanism of action of Aplidin involving p27 and support the analysis of p27 in the response to Aplidin in currently ongoing clinical trials to establish the levels of this protein as response predictor.
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PMID:Levels of p27(kip1) determine Aplidin sensitivity. 1743 Nov 9

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
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PMID:Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. 1743 Nov 20

Cyclooxygenase (COX-2) is overexpressed in human papillomavirus (HPV)-induced diseases, including cervical cancer. Although HPV E6 and E7 oncoproteins have been causally linked to cervical carcinogenesis, their effects on COX-2 gene expression are unknown. Increased levels of COX-2 mRNA, protein, and prostaglandin E(2) synthesis were detected in HPV16 E6- and E7-expressing cervical cancer cells (CaSki and SiHa) compared with an uninfected cervical cancer cell line (C33A). HPV16 E6 and E7 oncoproteins induced COX-2 transcription by activating the epidermal growth factor receptor (EGFR)-->Ras-->mitogen-activated protein kinase pathway. Interestingly, HPV16 oncoproteins stimulated EGFR signaling, in part, by inducing the release of amphiregulin, an EGFR ligand. The inductive effects of HPV16 E6 and E7 were mediated by enhanced binding of activator protein-1 to the cyclic AMP (cAMP)-responsive element (-59/-53) of the COX-2 promoter. The potential contribution of coactivators and corepressors to HPV16 E6- and E7-mediated induction of COX-2 was also investigated. Chromatin immunoprecipitation assays indicated that E6 and E7 oncoproteins induced the recruitment of phosphorylated c-Jun, c-Fos, UbcH5, and cAMP-responsive element binding protein-binding protein/p300 to the COX-2 promoter. In contrast, E6 and E7 inhibited the binding of the histone deacetylase 3-nuclear receptor corepressor (NCoR) complex to the COX-2 promoter. Moreover, overexpression of NCoR blocked E6- and E7-mediated stimulation of the COX-2 promoter. Taken together, these results indicate that HPV16 E6 and E7 oncoproteins stimulated COX-2 transcription by inducing a corepressor/coactivator exchange. To our knowledge, this study also provides the first evidence that NCoR can function as a repressor of COX-2 gene expression.
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PMID:Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence of a corepressor/coactivator exchange. 1744 Jan 14

Huntingon's disease is a progressive neurodegenerative disease arising from expansion of a polyglutamine (polyQ) tract in the protein huntingtin (Htt) resulting in aggregation of mutant Htt into nuclear and/or cytosolic inclusions in neurons. Mutant Htt affects multiple processes including protein degradation, transcription, signal transduction, fast axonal transport and endocytosis [reviewed in Ross, C.A. and Poirier, M.A. (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell. Biol., 6, 891-898]. Here, we report that the endocytic and signal transduction scaffold intersectin (ITSN) increased aggregate formation by mutant Htt through activation of the c-Jun-NH(2)-terminal kinase (JNK)-MAPK pathway. Conversely, silencing ITSN or inhibiting JNK attenuated aggregate formation. Using a Drosophila model for polyQ repeat disease, we observed that ITSN enhanced polyQ-mediated neurotoxicity. A reciprocal relationship was observed between ITSN and Htt. While ITSN enhanced Htt aggregation and toxicity, Htt, in turn, inhibited the cooperativity between ITSN and the epidermal growth factor receptor signal transduction pathway. Finally, we observed that ITSN overexpression enhanced aggregation of polyQ-expanded androgen receptor (AR) as well as wild-type versions of both Htt and AR suggesting a broader involvement of ITSN in neurodegenerative diseases through destabilization of polyQ-containing proteins.
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PMID:Intersectin enhances huntingtin aggregation and neurodegeneration through activation of c-Jun-NH2-terminal kinase. 1755 Sep 41

Cyclooxygenase-2 (COX-2) derived prostaglandins (PGs) are pathophysiological mediators in various disease states. Recently, we have demonstrated the rapid, epidermal growth factor receptor (EGFR)-dependent induction of COX-2 and PGE(2) synthesis in astrocytes following optic nerve injury and in culture. We have now investigated the signal transduction pathways activated by EGFR to accomplish the expression of COX-2 in primary optic nerve astrocytes. When astrocytes were exposed to EGF, marked, rapid gene expression of COX-2 was observed. Activation of EGFR caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 MAPK (p38) and c-Jun NH (2)-terminal kinase (JNK). Furthermore, U0126, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished EGF-induced COX-2 expression; whereas, a JNK inhibitor did not suppress COX-2 expression by EGF. Using inhibitors of several other signaling cascades, we found that, unlike epithelial and cancer cells, NF-kappaB, PI 3-kinase/Akt and PKC were not signaling pathways for EGFR-dependent induction of COX-2 in optic nerve astrocytes. Taken together, these data suggest that ERK and p38 are key components of the intracellular signaling switch that transduces EGFR activation into COX-2 induction and PGE(2) biosynthesis in optic nerve astrocytes.
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PMID:Signal transduction pathways for epidermal growth factor stimulated cyclooxygenase-2 induction in astrocytes. 1760 21

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.
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PMID:Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization. 1761 73

Many of the signaling responses induced by transforming growth factor-beta (TGF-beta) are mediated by Smad proteins, but there is evidence that it can also signal independently of Smads. Here, we provide evidence that multiple signal pathways induced by TGF-beta1-including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherin-dependent cell-cell interactions-transactivate the epidermal growth factor receptor (EGFR), which in turn regulates expression of c-Fos and c-Jun. Immunoprecipitation and immunofluorescence staining showed that EGFR was phosphorylated on tyrosine in response to TGF-beta1. EGFR transactivation required the activation of SFKs and the production of ROS via NADPH oxidase, but was not dependent on metalloproteases or the release of EGF-like ligands. In addition, the production of ROS was dependent on signaling by specific SFKs as well as de novo protein synthesis. Stable transfection of E-cadherin into MDA-MB-231 cells as well as E-cadherin-blocking assays revealed that E-cadherin-mediated cell-cell interactions were also essential for EGFR transactivation. Finally, EGFR transactivation was involved in the expression of c-Fos and c-Jun via the extracellular signal-regulated kinase signaling cascade. Taken together our data suggest that ligand release-independent transactivation of EGFR may diversify early TGF-beta signaling and represent a novel pathway leading to TGF-beta-mediated gene expression.
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PMID:Ligand release-independent transactivation of epidermal growth factor receptor by transforming growth factor-beta involves multiple signaling pathways. 1763 50


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