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)

The AP-1 transcription factor is a dimeric protein complex formed primarily between Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2) family members. These distinct AP-1 complexes are expressed in many cell types and modulate target gene expression implicated in cell proliferation, differentiation, and stress responses. Although the importance of AP-1 has long been recognized, the biochemical characterization of AP-1 remains limited in part due to the difficulty in purifying full-length, reconstituted dimers with active DNA-binding and transcriptional activity. Using a combination of bacterial coexpression and epitope-tagging methods, we successfully purified all 12 heterodimers (3 Junx4 Fos) of full-length human AP-1 complexes as well as c-Jun/c-Jun, JunD/JunD, and c-Jun/JunD dimers from bacterial inclusion bodies using one-step nickel-NTA affinity tag purification following denaturation and renaturation of coexpressed AP-1 subunits. Coexpression of two constitutive components in a dimeric AP-1 complex helps stabilize the proteins when compared with individual protein expression in bacteria. Purified dimeric AP-1 complexes are functional in sequence-specific DNA binding, as illustrated by electrophoretic mobility shift assays and DNase I footprinting, and are also active in transcription with in vitro-reconstituted human papillomavirus (HPV) chromatin containing AP-1-binding sites in the native configuration of HPV nucleosomes. The availability of these recombinant full-length human AP-1 complexes has greatly facilitated mechanistic studies of AP-1-regulated gene transcription in many biological systems.
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PMID:One-step affinity tag purification of full-length recombinant human AP-1 complexes from bacterial inclusion bodies using a polycistronic expression system. 1832 90

Alzheimer's disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebral vessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Abeta deposits evoke neuro- and neurovascular inflammation contributing to neurodegeneration. In this study, we found that exposure of cultured human brain endothelial cells (HBEC) to Abeta(1-40) elicited expression of inflammatory genes MCP-1, GRO, IL-1beta and IL-6. Up-regulation of these genes was confirmed in AD and AD/CAA brains by qRT-PCR. Profiling of 54 transcription factors indicated that AP-1 was strongly activated not only in Abeta-treated HBEC but also in AD and AD/CAA brains. AP-1 complex in nuclear extracts from Abeta-treated HBEC bound to AP-1 DNA-binding sequence and activated the reporter gene of a luciferase vector carrying AP-1-binding site from human MCP-1 gene. AP-1 is a dimeric protein complex and supershift assay identified c-Jun as a component of the activated AP-1 complex. Western blot analyses showed that c-Jun was activated via JNK-mediated phosphorylation, suggesting that as a result of c-Jun phosphorylation, AP-1 was activated and thus up-regulated MCP-1 expression. A JNK inhibitor SP600125 strongly inhibited Abeta-induced c-Jun phosphorylation, AP-1 activation, AP-1 reporter gene activity and MCP-1 expression in cells stimulated with Abeta peptides. The results suggested that JNK-AP1 signaling pathway is responsible for Abeta-induced neuroinflammation in HBEC and Alzheimer's brain and that this signaling pathway may serve as a therapeutic target for relieving Abeta-induced inflammation.
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PMID:Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway. 1916 85

Compound CU201 [SUIM-(d-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-d-Igl-Oic-Arg)(2), where SUIM=suberimidyl; Hyp=trans-4-hydroxyproline; Igl=alpha-(2-indanyl)-glycine; Oic=octahydroindole-2-carboxylic acid], is a dimeric analog of the potent bradykinin antagonist peptide B9430. It blocks the G(alphaq,11) signal of the heterotrimeric G proteins, stimulates c-Jun kinases, and induces apoptosis in lung cancer cells with neuroendocrine features. CU201 shows potent inhibition for small-cell lung cancer cells in vitro (ED(50)=0.15microM), as well as for small-cell lung cancer SHP-77 tumor growth in vivo. An HPLC method was developed, as part of a study supported by the National Cancer Institute's (NCI's) Rapid Access to Interventional Development (RAID) program, to assess the purity and stability of CU201. Impurities and degradation products were characterized by LC/MS. The identity of a major impurity, with 1 mass unit different from CU201, was confirmed by high resolution LC/MS and the investigation of model compounds. Susceptible linkages in the peptide chains were revealed by the degradation study.
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PMID:LC/MS characterization of impurities and degradation products of a potent antitumor peptidic dimer, CU201. 1989 31

The Fos family proteins, c-Fos and Fra-1, are components of the dimeric transcription factor AP-1, which is typically composed of Fos and Jun family proteins. We have previously shown that mice lacking c-Fos (Fos(-/-) mice) respond more strongly to LPS injection than do wild-type (wt) controls. We then examined the sensitivity of Fos(-/-) mice to acute inflammatory stress in a dextran sulfate sodium (DSS)-induced colitis model. We found that Fos(-/-) mice exhibited more severe weight loss, bleeding, diarrhea, and colon shortening than did wt mice, in association with higher TNF-alpha production and NF-kappaB activity in colon segments of DSS-treated Fos(-/-) mice. Furthermore, NF-kappaB inhibition suppressed severe DSS-induced colitis in Fos(-/-) mice. In contrast, Fra-1 transgenic (Tg) mice responded poorly to LPS injection, and Fra-1-overexpressing macrophages and fibroblasts showed reduced production of proinflammatory cytokines, NO, and NF-kappaB activity. Remarkably, in the DSS-induced colitis model, Fra-1 Tg mice showed less severe clinical scores of colitis than did wt mice. Consistently, proinflammatory cytokine production and NF-kappaB activity in colon segments of DSS-treated Fra-1 Tg mice were lower than in wt controls. These findings reveal that the absence of c-Fos and overexpression of Fra-1 respectively enhance and suppress the activation of NF-kappaB in DSS-induced inflammatory stress. In this paper, we propose that AP-1 transcription factors containing c-Fos or Fra-1 are negative regulators of NF-kappaB-mediated stress responses.
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PMID:Fos proteins suppress dextran sulfate sodium-induced colitis through inhibition of NF-kappaB. 2001 14

Multiple tumorigenic pathways converge on the activating protein-1 (AP-1) family of dimeric transcription complexes by affecting transcription, mRNA decay, posttranslational modifications, as well as stability of its JUN and FOS components. Several mechanisms have been implicated in the phosphorylation- and ubiquitylation-dependent control of c-Jun protein stability. Although its dimer composition has a major role in the regulation of AP-1, little is known about the influence of heterodimerization partners on the half-life of c-Jun. The FOS family member Fra-1 is overexpressed in various tumors and cancer cell lines wherein it controls motility, invasiveness, cell survival and cell division. Oncogene-induced accumulation of Fra-1 results from both increased transcription and phosphorylation-dependent stabilization of the protein. In this report, we describe a novel role of Fra-1 as a posttranslational regulator of c-Jun. By using both constitutively and inducible transformed rat thyroid cell lines, we found that c-Jun is stabilized in response to RAS oncoprotein expression. This stabilization requires the activity of the extracellular signal-related kinase (ERK) pathway, along with c-Jun heterodimerization with Fra-1. In particular, heterodimerization with Fra-1 inhibits c-Jun breakdown by a mechanism dependent on the phosphorylation of the Fra-1 C-terminal domain that positively controls the stability of the protein in response to ERK signaling. Therefore, Fra-1 modulates AP-1 dimer composition by promoting the accumulation of c-Jun in response to oncogenic RAS signaling.
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PMID:Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. 2054 61

Activator protein-1 (AP-1) regulates diverse gene responses triggered by environmental cues and virus-induced cellular stress. Although many signaling events leading to AP-1 activation have been described, the fundamental features underlying binding site selection and factor recruitment of dimeric AP-1 complexes to their target genes remain mostly uncharacterized. Using recombinant full-length human AP-1 dimers formed between c-Jun and Fos family members (c-Fos, FosB, Fra-1, Fra-2) for DNA binding and transcriptional analysis, we found that each of these AP-1 complex exhibits differential activity for distinct non-consensus AP-1 sites present in human papillomavirus (HPV), and each AP-1 complex is capable of activating transcription from in vitro-reconstituted HPV chromatin in a p300- and acetyl-CoA-dependent manner. Transcription from HPV chromatin requires AP-1-dependent and contact-driven recruitment of p300. Acetylation of dimeric AP-1 complexes by p300 enhances AP-1 binding to DNA. Using a human C-33A cervical cancer-derived cell line harboring the episomal HPV type 11 genome, we illustrate binding site selectivity recognized by c-Jun, JunB, JunD, and various Fos family members in a combinatorial and unique pattern, highlighting the diversity and importance of non-canonical binding site recognition by various AP-1 family proteins.
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PMID:Binding site specificity and factor redundancy in activator protein-1-driven human papillomavirus chromatin-dependent transcription. 2193 52

Recently, we showed that leucine zipper (LZ) motifs of basic leucine zipper (bZIP) transcription factors GCN4 and c-Jun are capable of catalyzing degradation of RNA (Nikolaev et al., PLoS ONE 2010; 5:e10765). This observation is intriguing given the tight regulation of RNA turnover control and the antiquity of bZIP transcription factors. To support further mechanistic studies, herein, we elucidated RNA binding interface of the GCN4 leucine zipper motif from yeast. Solution NMR experiments showed that the LZ-RNA interaction interface is located in the first two heptads of LZ moiety, and that only the dimeric (coiled coil) LZ conformation is capable of binding RNA. Site-directed mutagenesis of the LZ-GCN4 RNA binding interface showed that substrate binding is facilitated by lysine and arginine side chains, and that at least one nucleophilic residue is located in proximity to the RNA phosphate backbone. Further studies in the context of full-length bZIP factors are envisaged to address the biological relevance of LZ RNase activity.
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PMID:Structural basis of RNA binding by leucine zipper GCN4. 2237 68

c-Jun, the major component of the AP-1 transcription factor complex, has important functions in cellular proliferation and oncogenic transformation. The RING domain-containing protein RACO-1 functions as a c-Jun coactivator that molecularly links growth factor signalling to AP-1 transactivation. Here we demonstrate that RACO-1 is present as a nuclear dimer and that c-Jun specifically interacts with dimeric RACO-1. Moreover, RACO-1 is identified as a substrate of the arginine methyltransferase PRMT1, which methylates RACO-1 on two arginine residues. Arginine methylation of RACO-1 promotes a conformational change that stabilises RACO-1 by facilitating K63-linked ubiquitin chain formation, and enables RACO-1 dimerisation and c-Jun interaction. Abrogation of PRMT1 function impairs AP-1 activity and results in decreased expression of a large percentage of c-Jun target genes. These results demonstrate that arginine methylation of RACO-1 is required for efficient transcriptional activation by c-Jun/AP-1 and thus identify PRMT1 as an important regulator of c-Jun/AP-1 function.
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PMID:Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation. 2385 82

A surface-enhanced Raman scattering (SERS)-based sensor was developed for the detection of the oncoprotein c-Jun at nanomolar levels. c-Jun is a member of the bZIP (basic zipper) family of dimeric transcriptional activators, and its overexpression has been associated with carcinogenic mechanisms in several human cancers. For our sensing purpose, we exploited the ability of c-Jun to heterodimerize with its native protein partner, c-Fos, and therefore designed a c-Fos peptide receptor chemically modified to incorporate a thiophenol (TP) group at the N-terminal site. The TP functionality anchors the c-Fos protein onto the metal substrate and works as an effective SERS probe to sense the structural rearrangements associated with the c-Fos/c-Jun heterodimerization.
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PMID:Highly sensitive SERS quantification of the oncogenic protein c-Jun in cellular extracts. 2381 97

The transcription factor activator protein-1 (AP-1) participates in many aspects of cell physiology, such as cellular proliferation, transformation, and death. AP-1 is a dimeric complex that primarily contains Jun and Fos family members. Here, we report that JUN is a target of heat shock transcription factor HSF1. HSF1 is the master regulator of genes encoding molecular chaperones, and is involved in cellular processes such as the stress response, cell differentiation, aging and carcinogenesis. In HeLa cells, JUN transcription was rapidly induced by heat treatment. We found that HSF1 bound to the JUN promoter and was necessary for its efficient response to heat shock. In heat-shocked cells, c-Jun-mediated gene expression was induced slowly following accumulation of c-Jun protein. Forced expression of active HSF1 in cells resulted in an increase in c-Jun expression and activation of c-Jun target genes. These results show that HSF1 regulates JUN expression, thereby modulating AP-1 activity.
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PMID:The proto-oncogene JUN is a target of the heat shock transcription factor HSF1. 2412 37


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