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)

CCAAT/enhancer-binding proteins (C/EBPs) are basic region/leucine zipper transcription factors that function as regulators of cell growth and differentiation in numerous cell types. We previously localized transcriptional activation and inhibitory regions in one family member, C/EBP epsilon. Here we describe the further characterization of a C/EBP epsilon inhibitory domain termed regulatory domain I. We show that functionally related domains are present in C/EBP alpha, C/EBP beta, and C/EBP delta. These domains contain an evolutionarily conserved five-amino acid motif (the regulatory domain motif (RDM)) that conforms to the consensus sequence (I/V/L)KXEP. Mutagenesis studies revealed that the residues at positions 1, 2, and 4 of the RDM are critical for inhibitory domain function. Data base searches identified RDM-like sequences in a number of nuclear proteins. We found that small regions from c-Jun, JunB, and JunD containing this sequence also function as transcriptional inhibitory domains. Importantly, the RDM is similar to the recognition sequence for attachment of the ubiquitin-like protein, small ubiquitin-like modifier-1 (SUMO-1), and the conserved lysine residue of each C/EBP RDM served as an attachment site for SUMO-1. SUMO-1 attachment decreased the inhibitory effect of the C/EBP epsilon regulatory domain, suggesting that sumoylation may play an important role in modulating C/EBP epsilon activity as well as that of the other C/EBP family members.
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PMID:Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. 1216 47

Peptidoglycan-activated gene expression is mediated through various transcription factors including CCAAT/enhancer-binding protein delta (C/EBPdelta). The purpose of the present study is to elucidate the mechanism of PGN-activated C/EBPdelta gene. PGN stimulated C/EBPdelta protein and mRNA expression in mouse macrophages RAW 264.7 cells. Analysis of C/EBPdelta promoter activity by luciferase reporter assay indicated that PGN-induced C/EBPdelta gene activation is partially mediated by the -345 to +24 bp of C/EBPdelta gene promoter. The in vitro protein-DNA binding assay showed that Sp1, c-Rel and c-Jun are the major protein binding to this PGN-response element of C/EBPdelta promoter, and the binding of c-Rel and c-Jun is increased after PGN treatment. All of these binding activities were abolished when Sp1-, NF-kappaB/APRE-, CRE-sites were mutated. Furthermore, analysis of this promoter region by site-directed mutants constructed in luciferase reporter vector indicated that two Sp1-sites, one NF-kappaB/APRE-site and one CRE-site are prominent for PGN-induced gene expression. In addition, when Sp1, c-Rel or c-Jun transcription factors were overexpressed in cells, all of them enhanced C/EBPdelta promoter activity. In summary, we suggest that Sp1, c-Rel and c-Jun transcription factors play important roles in activation of C/EBPdelta gene promoter under the stimulation of PGN. Given the importance of C/EBPdelta in inflammatory disease, these results reveal a clue as a potential therapeutic target for suppression of C/EBPdelta expression under PGN stimulation.
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PMID:Peptidoglycan enhances transcriptional expression of CCAAT/enhancer-binding protein delta gene in mouse macrophages. 1727

Insulin-like growth factor 1 (IGF1) exerts important endocrine and paracrine functions in the cardiovascular system. We identified the common variant -1411C>T in the IGF1 upstream promoter P1, located within several overlapping transcription factor binding sites. Using transient transfection assays, we identified this site as a functional enhancer. The T allele-carrying enhancer, compared with the C allelic portion, exerts significantly reduced or even abrogated activity, respectively, in SaOs-2 and HepG2 (all P<0.0001) as well as in differentiated THP-1 macrophages. Electrophoretic mobility shift assay and subsequent supershift experiments in HepG2 identified c-Jun as the binding partner exclusively to the T allele, whereas CCAAT/enhancer-binding protein delta and interferon consensus site-binding protein/interferon-regulating factor 8 interacted only with the C allelic promoter portion. Furthermore, genotyping in a case-control study for essential hypertension (n=745 hypertensive patients; n=769 normotensive control subjects) for this variant revealed an odds ratio for hypertension of 0.73 (95% confidence interval 0.58-0.91, P=0.006) associated with the T allele, and normotensive subjects carrying the protective T allele displayed a significant decrease in diastolic (P=0.036) and systolic (P=0.024) blood pressure levels. We here report detection of a functional enhancer module in the upstream IGF1 promoter region, which might play a key role in local IGF1 bioavailability. Whether -1411C>T is also associated with other IGF1-related disease phenotypes should be evaluated further in population studies.
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PMID:Molecular genetic analysis of a human insulin-like growth factor 1 promoter P1 variation. 1910 45

Cyclooxygenase 2 (COX-2) is an important inflammatory factor. Previous studies have indicated that COX-2 is induced with lipopolysaccharide (LPS) treatment. Here, we found that an inhibitor of histone deacetylase (HDAC), trichostatin A (TSA), cannot repress LPS-induced COX-2 but it increased the COX-2 level in RAW264.7 cells. We found no significant difference in NF-kappaB activation and ERK1/2 phosphorylation, but LPS-induced C/EBP delta expression was completely abolished after TSA treatment of LPS-treated cells. Interesting, reporter assay of C/EBP delta promoter revealed that Sp1-binding site is important. Although there was no alteration in c-Jun levels, but the phosphorylation of c-Jun at its C-terminus was increased dramatically. A DNA-associated protein assay (DAPA) and chromatin immunoprecipitation assay (ChIP) indicated that c-Jun was recruited via Sp1 to the promoter of C/EBP delta after LPS treatment; this recruitment of c-Jun was repressed by TSA. C/EBP delta inhibition by TSA resulted in increased binding of C/EBP alpha and C/EBP beta to the COX-2 promoter. Therefore, TSA has a positive effect on LPS-induced COX-2 since it decreases the C/EBP delta level by reducing c-Jun recruitment by Sp1 to the C/EBP delta promoter, resulting in increased the recruitment of C/EBP alpha and C/EBP beta to the COX-2 promoter.
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PMID:Inhibition of LPS-induced C/EBP delta by trichostatin A has a positive effect on LPS-induced cyclooxygenase 2 expression in RAW264.7 cells. 2050 44