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)

Tumor necrosis factor alpha (TNF alpha) is a key regulatory cytokine whose expression is controlled by a complex set of stimuli in a variety of cell types. Previously, we found that the monocyte/macrophage-enriched nuclear transcription factor C/EBPbeta played an important role in the regulation of the TNF alpha gene in myelomonocytic cells. Abundant evidence suggests that other transcription factors participate as well. Here we have analyzed interactions between C/EBPbeta and c-Jun, a component of the ubiquitously expressed AP-1 complex. In phorbol myristate acetate (PMA)-treated Jurkat T cells, which did not possess endogenous C/EBPbeta, expression of c-Jun by itself had relatively little effect on TNF alpha promoter activity. However, the combination of C/EBPbeta and c-Jun was synergistic, resulting in greater than 130-fold activation. This effect required both the leucine zipper and DNA binding domains, but not the transactivation domain, of c-Jun, plus the AP-1 binding site centered 102/103 bp upstream of the transcription start site in the TNF alpha promoter. To determine if C/EBPbeta and c-Jun might cooperate to regulate the cellular TNF alpha gene in myelomonocytic cells, U937 cells that possess endogenous C/EBPbeta and were stably transfected with either wild-type c-Jun or the transactivation domain deletion mutant (TAM-67) were examined. U937 cells expressing ectopic wild-type c-Jun or TAM-67 secreted over threefold more TNF alpha than the control line in response to PMA plus lipopolysaccharide. Transient transfection of the U937 cells expressing TAM-67 suggested that TAM-67 binding to the -106/-99-bp AP-1 binding site cooperated with endogenous C/EBPbeta in the activation of the -120 TNF alpha promoter-reporter. DNA binding assays using oligonucleotides derived from the TNF alpha promoter suggested that C/EBPbeta and c-Jun interact in vitro and that the interaction may be DNA dependent. Our data demonstrate that the TNF alpha gene is regulated by the interaction of the ubiquitous AP-1 complex protein c-Jun and the monocyte/macrophage-enriched transcription factor C/EBPbeta and that this interaction contributes to the expression of the cellular TNF alpha gene in myelomonocytic cells. This interaction was unique in that it did not require the c-Jun transactivation domain, providing new insight into the cell-type-specific regulation of the TNF alpha gene.
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PMID:Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun. 956

The transcription factor C/EBPalpha is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and C/EBPalpha can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPalpha knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPalpha knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPalpha downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPalpha expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPalpha. C/EBPalpha and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPalpha-induced granulocytic differentiation. Thus, we propose a model in which C/EBPalpha needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.
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PMID:Downregulation of c-Jun expression by transcription factor C/EBPalpha is critical for granulocytic lineage commitment. 1244 86

Small intestinal ulceration, bleeding, and inflammation are major adverse effects associated with the use of diclofenac (DCF) or other nonsteroidal anti-inflammatory drugs (NSAIDs). The underlying mechanisms of DCF enteropathy are poorly understood, but there is increasing evidence that topical effects are involved. The aim of this study was to explore the role of c-Jun-N-terminal kinase (JNK) in DCF-induced enterocyte death because JNK not only regulates mitochondria-mediated apoptosis but also is a key node where many of the proximal stress signals converge. Male C57BL/6J mice were injected intraperitoneally with DCF or vehicle (Solutol HS-15), and the extent of small intestinal ulceration was determined. A single dose of DCF (60 mg/kg) produced numerous ulcers in the third and fourth quartiles of the jejunum and ileum, with maximal effects after 18 h and extensive recovery after 48 h. To study the molecular pathways leading to enterocyte injury, we isolated villi-enriched mucosal fractions from DCF-treated mice. Immunoblot studies with a phosphospecific JNK antibody revealed that JNK1/2 (p46) was activated at 6 h, leading to phosphorylation of the downstream target c-Jun. The levels of the JNK-regulated proapoptotic transcription factor C/EBP homologous protein (CHOP) were also increased after DCF. The selective JNK inhibitor SP600125 (30 mg/kg ip), given both 1 h before and 1 h after DCF, blocked JNK kinase activity and afforded significant protection against DCF enteropathy. In conclusion, these data demonstrate that the JNK pathway is critically involved in the pathogenesis of DCF-induced enteropathy and suggest a potential application of JNK inhibitors in the prevention of NSAID-induced enteropathy.
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PMID:Protection from diclofenac-induced small intestinal injury by the JNK inhibitor SP600125 in a mouse model of NSAID-associated enteropathy. 2050 47