Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1-/- mice) or TNFR2 (TNFR2-/- mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1-/- and TNFR2-/- mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1-/- mice were markedly more resistant to tumour development than TNFR2-/- mice indicating that TNFR1 is the major mediator of TNF-alpha-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1-/- and TNFR2-/- compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. These genes were differentially regulated in TNFR1-/- compared to TNFR2-/- epidermis, suggesting that the TNF-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.
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PMID:Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. 1466 Oct 63

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

Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in the initiation of T cell-dependent immune responses. Immature DCs obtained from peripheral blood CD14+ monocytes by culture with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) differentiate into mature DCs upon stimulation with lipopolysaccharide (LPS). At least three families of mitogen-activated protein kinases (MAPKs), that is, extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38 MAPK, are involved in the DC maturation process. We report investigations of the role of JNK in the maturation of human monocyte-derived DCs. SP600125, a specific inhibitor of JNK, inhibited the LPS-induced up-regulation of CD80, CD83, CD86 and CD54, but augmented the up-regulation of HLA-DR. SP600125 slightly inhibited the down-regulation of FITC-dextran uptake during DC maturation. However, SP600125 did not affect the LPS induced up-regulation of allostimulatory capacity of DCs. SP600125 inhibited the release of IL-12 p70 and TNF-alpha from mature DCs. Although autologous T cells primed by the ovalbumin (OVA)-pulsed mature DCs produced IFN-gamma, but not IL-4, OVA-pulsed SP600125-treated mature DCs could initiate IL-4 production from autologous T cells. In contrast, a p38 MAPK inhibitor, SB203580, profoundly inhibited the phenotypic and functional maturation of DCs, while an ERK inhibitor, PD98059, had little or no effect. Taken together, the JNK signaling pathway appears to have a role that is distinct from the p38 MAPK and ERK cascades in the maturation process of DCs, and may be involved in the augmentation of Th2-prone T cell responses when it is suppressed.
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PMID:Role of c-Jun N-terminal kinase on lipopolysaccharide induced maturation of human monocyte-derived dendritic cells. 1547 28

Chlamydophila pneumoniae is an important respiratory pathogen. In this study we characterized C. pneumoniae strain TW183-mediated activation of human small airway epithelial cells (SAEC) and the bronchial epithelial cell line BEAS-2B and demonstrated time-dependent secretion of granulocyte macrophage colony-stimulating factor (GM-CSF) upon stimulation. TW183 activated p38 mitogen-activated protein kinase (MAPK) in epithelial cells. Kinase inhibition by SB202190 blocked Chlamydia-mediated GM-CSF release on mRNA and protein levels. In addition, the chemical inhibitor as well as dominant-negative mutants of p38 MAPK isoforms p38alpha, beta2, and gamma inhibited C. pneumoniae-related NF-kappaB activation. In contrast, blocking of MAPK ERK, c-Jun kinase/JNK, or PI-3 Kinase showed no effect on Chlamydia-related epithelial cell GM-CSF release. Ultraviolet-inactivated pathogens as compared with viable bacteria induced a smaller GM-CSF release, suggesting that viable Chlamydiae were only partly required for a full effect. Presence of an antichlamydial outer membrane protein-A (OmpA) antibody reduced and addition of recombinant heat-shock protein 60 from C. pneumoniae (cHsp60, GroEL-1)-enhanced GM-CSF release, suggesting a role of these proteins in epithelial cell activation. Our data demonstrate that C. pneumoniae triggers an early proinflammatory signaling cascade involving p38 MAPK-dependent NF-kappaB activation, resulting in subsequent GM-CSF release. C. pneumoniae-induced epithelial cytokine liberation may contribute significantly to inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) or bronchial asthma.
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PMID:Mechanisms of Chlamydophila pneumoniae-mediated GM-CSF release in human bronchial epithelial cells. 1634 3

C/EBPalpha is required for generation of granulocyte-monocyte progenitors, but the subsequent role of C/EBPalpha in myeloid lineage commitment remains uncertain. We transduced murine marrow cells with C/EBPalpha-estradiol receptor (ER) or empty vector and subjected these to lineage depletion just prior to culture in estradiol with myeloid cytokines. This protocol limits biases due to lineage-specific effects on developmental kinetics, proliferation, and apoptosis. Also, lowering the dose of estradiol reduced activated C/EBPalpha-ER to near the physiologic range. C/EBPalpha-ER increased Mac1(+)/Gr1(-)/MPO(-)/low monocytes 1.9-fold while reducing Mac1(+)/Gr1(+)/MPO(hi) granulocytes 2.5-fold at 48 hours, even in 0.01 microM estradiol. This pattern was confirmed morphologically and by quantitative polymerase chain reaction (PCR) assay of lineage markers. To directly assess effects on immature progenitors, transduced cells were cultured for 1 day with and then in methylcellulose without estradiol. A 2-fold increase in monocytic compared with granulocytic colonies was observed in IL-3/IL-6/SCF or GM-CSF, but not G-CSF, even in 0.01 microM estradiol. C/EBPalpha-ER induced PU.1 mRNA, and PU.1-ER stimulated monocytic development, suggesting that transcriptional induction of PU.1 by C/EBPalpha contributes to monopoiesis. A C/EBPalpha variant incapable of zippering with c-Jun did not induce monopoiesis, and a variant unable to bind NF-kappaB p50 stimulated granulopoiesis, suggesting their cooperation with C/EBPalpha during monocytic commitment.
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PMID:C/EBPalpha directs monocytic commitment of primary myeloid progenitors. 1664 68

Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-alpha (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli- or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3alpha-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus-triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages.
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PMID:G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages. 1688 27

PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor (LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitor. The CCAAT/enhancer-binding protein (C/EBP)alpha then directs the LMP to the granulocyte-monocyte progenitor (GMP) stage, while inhibiting lymphoid development via cross-inhibition of Pax5 and potentially other regulators. Increased PU.1 activity favors monocytic commitment of the GMP. Induction of PU.1 by C/EBPalpha and interaction of PU.1 with c-Jun elevates PU.1 activity. Zippering of C/EBPalpha with c-Jun or c-Fos also contributes to monocyte lineage specification. An additional factor, potentially an Id1-regulated basic helix-loop-helix protein, may be required for the GMP to commit to the granulocyte lineage. Egr-1, Egr-2, Vitamin D Receptor, MafB/c: Fos and PU.1:interferon regulatory factor 8 complexes direct further monocytic maturation, while retinoic acid receptor (RAR) and C/EBPepsilon direct granulopoiesis. Both C/EBPalpha and RARs induce C/EBPepsilon, and PU.1 is also required, albeit at lower levels, for granulocytic maturation. HoxA10 and CAAT displacement protein act as transcriptional repressors to delay expression of terminal differentiation. Gfi-1 and Egr-1,2/Nab2 complexes repress each other to maintain myeloid lineage fidelity. NF-kappaB directly binds and cooperates with C/EBPbeta to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/EBPalpha to regulate early myelopoiesis.
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PMID:Transcriptional control of granulocyte and monocyte development. 1793 88

Mef2c is a MADS (MCM1-agamous-deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2c(Delta/-) mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBPalpha, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity--and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.
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PMID:The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate. 1832 19

Basophils are the accessory cell type for T-helper (Th)2 induction and initiators in immunoglobulin E-mediated chronic allergic inflammation. Basophils and Th17 cells accumulate at the inflammatory sites, such as the airways of allergic asthmatic patients. We investigated the activation of interleukin (IL)-17A on the primary human basophils/KU812 basophilic cells and primary human bronchial epithelial cells/BEAS-2B bronchial epithelial cells. Cytokines, chemokines, adhesion molecules and intracellular signalling molecules were assayed by ELISA or flow cytometry. Co-culture of bronchial epithelial cells and basophils could significantly induce the release of IL-6, an epithelial inflammatory cytokine, and CCL2, a chemokine for basophils, esosinophils and monocytes. Such induction was synergistically enhanced by IL-17A, and direct interaction between these two cells was necessary for IL-17A-induced IL-6 and CCL2 release. Surface expression of intercellular adhesion molecule-1 on bronchial epithelial cells was also upregulated upon their interaction. The interaction of basophils and bronchial epithelial cells under IL-17A stimulation was differentially regulated by extracellular signal-regulated kinase, c-Jun N-terminal protein kinase, p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. These findings suggest a novel immunopathological role of Th17 cells and basophils in allergic asthma through the activation of granulocyte-mediated inflammation initiated by the direct interaction between basophils and bronchial epithelial cells.
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PMID:Interleukin-17A activation on bronchial epithelium and basophils: a novel inflammatory mechanism. 1974 Oct 26

The transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha) has an important role in granulopoiesis. The tumor suppressor function of C/EBPalpha is shown by the findings that loss of expression or function of C/EBPalpha in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPalpha mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPalpha (C/EBPalpha-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPalpha-p30 in AML. In the present study, we show that C/EBPalpha-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPalpha-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPalpha mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPalpha. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPalpha mutation.
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PMID:Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. 2037 80


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