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)

Cardiac myocyte survival is of central importance in the maintenance of the function of heart, as well as in the development of a variety of cardiac diseases. To understand the molecular mechanisms that govern this function, we characterized apoptosis in cardiac muscle cells following serum deprivation. Cardiotrophin 1 (CT-1), a potent cardiac survival factor (Sheng, Z., Pennica, D., Wood, W. I., and Chien, K. R. (1996) Development (Camb.) 122, 419-428), is capable of inhibiting apoptosis in cardiac myocytes. To explore the potential downstream pathways that might be responsible for this effect, we documented that CT-1 activated both signal transducer and activator of transcription 3 (STAT3)- and mitogen-activated protein (MAP) kinase-dependent pathways. The transfection of a MAP kinase kinase 1 (MEK1) dominant negative mutant cDNA into myocardial cells blocked the antiapoptotic effects of CT-1, indicating a requirement of the MAP kinase pathway for the survival effect of CT-1. A MEK-specific inhibitor (PD098059) (Dudley, D. T., Pang, L., Decker, S.-J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. USA 92, 7686-7689) is capable of blocking the activation of MAP kinase, as well as the survival effect of CT-1. In contrast, this inhibitor did not block the activation of STAT3, nor did it have any effect on the hypertrophic response elicited following stimulation of CT-1. Therefore, CT-1 promotes cardiac myocyte survival via the activation of an antiapoptotic signaling pathway that requires MAP kinases, whereas the hypertrophy induced by CT-1 may be mediated by alternative pathways, e.g. Janus kinase/STAT or MEK kinase/c-Jun NH2-terminal protein kinase.
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PMID:Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. 903 92

Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain. The entire extracellular domain of the GHR was replaced by the hemagglutinin-tagged zipper sequence of either the c-Fos or c-Jun transcription factor (termed Fos-GHR and Jun-GHR, respectively). Transient transfection of Fos-GHR or Jun-GHR resulted in activation of the serine protease inhibitor 2.1 promoter in Chinese hamster ovary-K1 cells to a level equal to that achieved by fully activated wild type GHR. Furthermore, stable expression of Jun-GHR alone or Fos-GHR and Jun-GHR together in the interleukin 3-dependent BaF-B03 cell line resulted in cell proliferation after interleukin 3 withdrawal at a rate equal to maximally stimulated wild type GHR-expressing cells. Activation of STAT 5b was also observed in Fos-Jun-GHR-expressing cells at a level equal to that in chronically GH-treated GHR-expressing cells. Thus, forced dimerization of the transmembrane and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have particular utility for transgenic livestock applications.
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PMID:Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation. 1082 73

Complete activation of signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Y701 and a conserved PMS(727)P sequence. S727 phosphorylation of STAT1 in interferon-gamma (IFN-gamma)-treated mouse fibroblasts occurred without a need for p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 or c-Jun kinases, and required both an intact SH2 domain and phosphorylation of Y701. In contrast, UV irradiation-induced STAT1 phosphorylation on S727 required p38MAPK, but no SH2 domain- phosphotyrosine interactions. Mutation of S727 differentially affected IFN-gamma target genes, at the level of both basal and induced expression. Particularly strong effects were noted for the GBP1 and TAP1 genes. The PMS(727)P motif of STAT3 was phosphorylated by stimuli and signaling pathways different from those for STAT1 S727. Transfer of the STAT3 C-terminus to STAT1 changed the stimulus and pathway specificity of STAT1 S727 phosphorylation to that of STAT3. Our data suggest that STAT C-termini contribute to the specificity of cellular responses by linking individual STATs to different serine kinase pathways and through an intrinsically different requirement for serine phosphorylation at different target gene promoters.
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PMID:Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression. 1122 59

Stat3 is a latent transcription factor activated by various cytokines and growth factors. Phosphorylation on Tyr-705 is a prerequisite for dimer formation, nuclear translocation, binding to its cognate DNA sequences, and regulation of the target gene transcription. Ser-727 phosphorylation of Stat3 plays an additional role in the regulation of transcription. MEK kinase 1 (MEKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) that activates the c-Jun NH(2)-terminal kinase signaling pathway. Here we report that MEKK1 is involved in the regulation of Stat3 activation by growth factors. Kinase-inactive MEKK1 inhibits Stat3 phosphorylation on tyrosine and serine, and its transcriptional activity stimulated by epidermal growth factor and platelet-derived growth factor in different cell types. In contrast, active MEKK1 induces Stat3 tyrosine and serine phosphorylation leading to a functionally active Stat3 capable of binding DNA and enhancing transcription. Ser-727 is phosphorylated by MEKK1 in vitro, whereas Tyr-705 phosphorylation induced by MEKK1 involves Src and Janus kinases in vivo. These data demonstrate for the first time a novel role of MEKK1 to modulate tyrosine kinases that results in the activation of specific members of STAT family.
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PMID:Regulation of Stat3 activation by MEK kinase 1. 1127 53

Cooperation between STAT3 and c-Jun results in suppression of Fas Receptor (FasR) transcription, which is often seen in advanced human tumors. To identify requirements for STAT3-Jun cooperation, we elucidated the role of protein kinases that affect both transcription factors. The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway was found capable of down-regulating both STAT3- and c-Jun-dependent transcription, resulting in derepression of FasR transcription. Conversely, inhibition of PI3K-AKT signaling via the specific pharmacological inhibitor LY294002 up-regulated AP1/Jun- and STAT-dependent transcriptional activities, resulting in suppression of the FasR promoter activities and decreased FasR surface expression. PI3K-AKT's ability to affect FasR transcription was not observed in c-jun null fibroblasts, suggesting that c-Jun is required for PI3K/AKT-mediated regulation of FasR transcription. Interestingly, the dominant negative form of Rac1 (RacN17) was also efficient in relieving FasR expression, suggesting that the increase in FasR expression following AKT stimuli could be mediated via AKT ability to elicit suppression of Rac1, which in turn decreases JNK activities and c-Jun phosphorylation. Overall, our findings demonstrate that through its negative effects on both c-Jun and STAT3, the PI3K-AKT pathway disrupts cooperation between c-Jun and STAT3, which is required for silencing the FasR promoter, resulting in increased expression of surface FasR and concomitant sensitization to FasL-mediated programmed cell death.
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PMID:Regulation of Fas expression by STAT3 and c-Jun is mediated by phosphatidylinositol 3-kinase-AKT signaling. 1173 15

Overexpression of the inducible cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in activated brain macrophages (microglia) and astrocytes appears central to many neuroinflammatory conditions. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma. It has been proposed as an inhibitor of microglial activation, based on the study of iNOS down-regulation in rodent microglia. Because iNOS induction after cytokine activation remains controversial in human microglia, we examined the effect of 15d-PGJ(2) and other PPAR agonists on human microglia and astrocytes, using COX-2 induction as an index of activation. We found that PPAR alpha ligands (clofibrate and WY14643) enhanced IL-1 beta-induced COX-2 expression in human astrocytes and microglia, while inhibiting IL-1 beta plus IFN-gamma induction of iNOS in astrocytes. This is the first description of an inhibition of iNOS uncoupled from that of COX-2. 15d-PGJ(2) suppressed COX-2 induction in human astrocytes. It prevented NF-kappa B binding to the COX-2 promoter through a new pathway that is the repression of NF-kappa Bp50 induction by IL-1 beta. In contrast, 15d-PGJ(2) increased c-Jun and c-Fos DNA-binding activity in astrocytes, which may result in the activation of other inflammatory pathways. In human microglia, no effect of 15d-PGJ(2) on COX-2 and NF-kappa Bp65/p50 induction was observed. However, the entry of 15d-PGJ(2) occurred in microglia because STAT-1 and c-Jun expression was modulated. Our data suggest the existence of novel pathways mediated by 15d-PGJ(2) in human astrocytes. They also demonstrate that, unlike astrocytes and peripheral macrophages or rodent brain macrophages, human microglia are not subject to the anti-inflammatory effect of 15d-PGJ(2) in terms of COX-2 inhibition.
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PMID:Selective inhibition of cyclooxygenase-2 expression by 15-deoxy-Delta(12,14)(12,14)-prostaglandin J(2) in activated human astrocytes, but not in human brain macrophages. 1197 Oct 25

Interferon-gamma (IFN-gamma) is required for induction of the human nitric oxide synthase-2 (NOS2) gene in lung epithelium. Although the human NOS2 promoter region contains many cytokine-responsive elements, the molecular basis of induction is only partially understood. Here, the major cis-regulatory elements that control IFN-gamma-inducible NOS2 gene transcription in human lung epithelial cells are identified as composite response elements that bind signal transducer and activator of transcription 1 (STAT-1) and activator protein 1 (AP-1), which is comprised of c-Fos, Fra-2, c-Jun, and JunD. Notably, IFN-gamma activation of the human NOS2 promoter is shown to require functional AP-1 regulatory region(s), suggesting a role for AP-1 activation/binding in the IFN-gamma induction of genes. We show that c-Fos interacts with STAT-1 after IFN-gamma activation and the c-Fos/STAT-1 complex binds to the gamma-activated site (GAS) element in close proximity to AP-1 sites located at 4.9 kb upstream of the transcription start site. Taken together, our findings support a model in which a physical interaction between c-Fos and STAT-1 participates in NOS2 gene transcriptional activation.
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PMID:STAT-1 and c-Fos interaction in nitric oxide synthase-2 gene activation. 1278 89

We have previously shown that the nonstructural (NS) proteins NS1 and NS2 of bovine respiratory syncytial virus (BRSV) mediate resistance to the alpha/beta interferon (IFN)-mediated antiviral response. Here, we show that they, in addition, are able to prevent the induction of beta IFN (IFN-beta) after virus infection or double-stranded RNA stimulation. In BRSV-infected MDBK cells upregulation of IFN-stimulated genes (ISGs) such as MxA did not occur, although IFN signaling via JAK/STAT was found intact. In contrast, infection with recombinant BRSVs lacking either or both NS genes resulted in efficient upregulation of ISGs. Biological IFN activity and IFN-beta were detected only in supernatants of cells infected with the NS deletion mutants but not with wild-type (wt) BRSV. Subsequent analyses of IFN-beta promoter activity showed that infection of cells with the double deletion mutant BRSV DeltaNS1/2, but not with BRSV wt, resulted in a significant increase in IFN-beta gene promoter activity. Induction of the IFN-beta promoter depends on the activation of three distinct transcription factors, NF-kappaB, ATF-2/c-Jun, and IFN regulatory factor 3 (IRF-3). Whereas NF-kappaB and ATF-2/c-Jun activities were readily detectable and comparable in both wt BRSV- and BRSV DeltaNS1/2-infected cells, phosphorylation and transcriptional activity of IRF-3, however, were observed only after BRSV DeltaNS1/2 infection. NS protein-mediated inhibition of IRF-3 activation and IFN induction should have considerable impact on the pathogenesis and immunogenicity of BRSV.
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PMID:Nonstructural proteins NS1 and NS2 of bovine respiratory syncytial virus block activation of interferon regulatory factor 3. 1288 84

Angiotensin II (Ang II) exerts a potent growth stimulus on the heart and vascular wall. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) intracellular signaling pathway by Ang II mediates at least some of the mitogenic responses to this hormone. In other signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study it is demonstrated that SOCS3 is constitutively expressed at a low level in rat heart and neonatal rat ventricular myocytes. Ang II at a physiological concentration enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide to SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-Jun expression after repetitive infusions of the hormone. Thus, SOCS3 is induced by Ang II in rat heart and neonatal rat ventricular myocytes and participates in the modulation of the signal generated by this hormone.
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PMID:Suppressor of cytokine signaling 3 is induced by angiotensin II in heart and isolated cardiomyocytes, and participates in desensitization. 1296 61

It has been shown that glutathione S-transferase pi (GSTpi) interacts with and suppresses the activity of c-Jun NH(2)-terminal kinase (JNK). GST-deficient mice (GSTpi(-/-)) have higher levels of circulating white blood cells, with similar proportions of lymphocytes, monocytes, and granulocytes. Interestingly, a selective expansion of splenic B lymphocytes was observed in GSTpi(-/-) animals but no change in T lymphocytes or natural killer cells. A peptidomimetic inhibitor of GSTpi that disrupts the interaction between GSTpi and JNK mimics in wild type mice the increased myeloproliferation observed in GSTpi(-/-) animals. Until now, the molecular basis for this effect has not been defined. In an in vitro hematopoiesis assay, interleukin-3, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor were more effective at stimulating proliferation of hematopoietic cells in GSTpi(-/-) mice than in wild type. The JNK inhibitor SP600125 which caused little inhibition of cytokine-induced myeloproliferation in wild type mice, decreased the number of colonies in GSTpi(-/-) animals. A more sustained phosphorylation of the STAT family of proteins was also observed in GSTpi(-/-) bone marrow-derived mast cells exposed to interleukin-3. This was associated with an increased proliferation and a down-regulation of expression of negative regulators of the Janus kinase-STAT pathway SHP, Src homology 2 domain-containing tyrosine phosphatase-1 and -2. The increased activation of JNK and STATs in GSTpi-deficient mice provides a viable mechanism for the increased myeloproliferation in these animals. These data also confirm the important role that GSTpi plays in the regulation of cell signaling pathways in a myeloproliferative setting.
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PMID:Increased myeloproliferation in glutathione S-transferase pi-deficient mice is associated with a deregulation of JNK and Janus kinase/STAT pathways. 1468 49


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