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)

UV irradiation is a major insult to the skin. We have shown previously that exogenous vitamin C (ascorbate) accumulates in HaCaT keratinocytes, thus conferring the ability to prevent radical formation and cell death elicited by UV-B. Here, we have investigated the potential mechanisms accounting for the cytoprotective effects exerted by this antioxidant. Using a cDNA microarray hybridization, we identified several genes whose expression was up-regulated by ascorbate. We focused on the fra-1 gene, a member of the Fos family of transcription factors that down-regulates activator protein-1 (AP-1) target genes. Both in HaCaT and in normal human epidermal keratinocytes, we found Fra-1 mRNA induction as early as 2 h after ascorbate loading. Electrophoretic mobility-shift assay and antibody supershift analysis revealed that ascorbate modulates AP-1 DNA-binding activity and that Fra-1 is in AP-1 complexes in treated cells. Furthermore, transient-transfection studies, using an AP-1 reporter construct, showed that ascorbate was able to inhibit both basal and UV-B-induced AP-1-dependent transcription. Ascorbate also modulates UV-B-induced AP-1 activity by preventing the phosphorylation and activation of the upstream c-Jun N-terminal kinase (JNK), thus inhibiting phosphorylation of the endogenous c-Jun protein. These data suggest that ascorbate mediates cellular responses aimed at counteracting UV-mediated cell damage and cell death by interfering at multiple levels with the activity of the JNK/AP-1 pathway and modulating the expression of AP-1-regulated genes.
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PMID:Induction of gene expression via activator protein-1 in the ascorbate protection against UV-induced damage. 1133 38

In the peripheral nervous system, triiodothyronine (T3) plays an important role in the development and regeneration of nerve fibers and in myelin formation. However, the target genes of T3 in peripheral nerves remain to be identified. We investigated whether T3 activated genes of transcription factors in Schwann cells. Expression of egr-1 (krox-24), egr-2 (krox-20), egr-3, c-jun, junB, c-fos, fosB, fra-1, fra-2, and CREB genes was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in Schwann cells isolated from neonatal rat sciatic nerves and in the cell lines MSC-80 (mouse Schwann cells), NIH-3T3 (mouse fibroblasts), and CHO (Chinese hamster ovary cells). Some of these transcription factors have been shown to be involved in Schwann cell differentiation. T3 triggered a rapid (15-30 min), transient (1-2-h) and strong (6- to 15-fold) stimulation of Egr-1, Egr-2, Egr-3, Jun B, c-Fos, and Fos B mRNA expression in Schwann cells. In contrast, expression of c-Jun, Fra-1, Fra-2, and CREB mRNA was not affected by T3. The stimulatory effects of T3 could be abolished by adding actinomycin D. T3 triggered the same pattern of gene stimulation in the mouse Schwann cell line MSC80, but not in the NIH-3T3 and CHO cell lines. Serum activated all the genes that responded to T3 and in addition fra-1 and fra-2, but not c-jun and CREB. Immunoblotting showed that the increase in Egr-1 and c-Fos mRNA levels was accompanied by an increase in the corresponding proteins. In addition, shifts of the protein bands indicated a posttranslational modification of the two proteins. These effects of T3 are likely to be mediated by the intracellular T3 receptor, as the D-isomer RT3 and T0, which do not bind to T3 receptors, proved ineffective. The present data suggested that T3 may regulate Schwann cell functions and differentiation by transiently activating the expression of specific transcription factors.
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PMID:Rapid effects of triiodothyronine on immediate-early gene expression in Schwann cells. 1146 Feb 64

Mesothelioma is a unique and insidious tumor associated historically with occupational exposure to asbestos. The transcription factor, activator protein-1 (AP-1) is a major target of asbestos-induced signaling pathways. Here, we demonstrate that asbestos-induced mesothelial cell transformation is linked to increases in AP-1 DNA binding complexes and the AP-1 component, Fra-1. AP-1 binding to DNA was increased dramatically in mesothelioma cell lines in comparison to isolated rat pleural mesothelial (RPM) cells. Elevated levels of AP-1 complexes, including significant increases in c-Jun, JunB and Fra-1, were found in asbestos-exposed RPM cells, but only Fra-1 expression was significantly increased and protracted in both asbestos-exposed RPM cells and mesothelioma cell lines. Asbestos-induced Fra-1 expression in RPM cells was dependent on stimulation of the extracellular signal-regulated kinases (ERKs 1/2). Inhibition of ERK phosphorylation or transfection with dominant-negative fra-1 constructs reversed the transformed phenotype of mesothelioma cells and anchorage-independent growth in soft agar. In summary, we demonstrate that ERK-dependent Fra-1 is elevated in AP-1 complexes in response to asbestos fibers and is critical to the transformation of mesothelial cells.
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PMID:Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. 1241 30

Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein 1 (AP1), in toxicant-induced epithelial injury, repair, and cellular transformation. Here, we have investigated the transcriptional regulation of fra-1 by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human bronchial epithelial (HBE) cells, which are the direct targets of inhaled toxins/carcinogens. In contrast to a transient induction by H2O2, TPA persistently activated fra-1 transcription, principally at the transcriptional level. A deletion analysis of the fra-1 promoter revealed that several cis-elements located between -105/+32 and -283/-105 bp mediate minimal and basal promoter activities, respectively. A region between -379 and -283 bp, which harbors a putative TPA response element, a GC box, and an Ets-like binding site, was required for high level TPA-inducible expression. Mutations in any of these cis-elements markedly reduced both basal and TPA-inducible expression. Thus, cooperative interactions between factors binding to multiple cis-elements of the -379/-283 promoter region appear to regulate TPA-induced fra-1 transcription in HBE cells. Consistent with this finding, electrophoretic mobility shift assays indicated the formation of multiple complexes consisting of the AP1-, Sp-, and ETS-specific family of transcription factors with the -379/-283 fragment. Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. Chromatin immunoprecipitation assays revealed an enhanced recruitment of c-Jun, Jun-D, and Fra-2 to the endogenous fra-1 promoter upon TPA stimulation. These results underscore the regulatory role of c-Jun, Jun-D, and Fra-2 in TPA-inducible fra-1 expression in HBE cells in vivo.
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PMID:Multiple cis-elements mediate the transcriptional activation of human fra-1 by 12-O-tetradecanoylphorbol-13-acetate in bronchial epithelial cells. 1367 79

Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein (AP)-1, in toxicant-induced epithelial injury, repair, and cellular transformation. Here we have investigated the effects of diesel exhaust particles (DEP) on fra-1 expression in C10 cells, a murine lung epithelial cell line. DEP markedly upregulated fra-1, but not fra-2, expression. The increase in fra-1 mRNA expression correlated well with its protein- and DNA-binding activity. DNA-binding assays also revealed a predominant presence of Jun-B and Jun-D in the AP-1 complex. Interestingly, DEP did not alter Jun-B and Jun-D protein levels. Transcriptional analysis revealed that fra-1 induction is regulated in part at the transcriptional level. The -379 to +32 bp 5'-flanking region mediated this induction. Furthermore, inhibitors of ERK1/2, JNK1, and p38 mitogen-activated protein kinases (MAPKs) significantly suppressed DEP-stimulated fra-1 transcription, suggesting their involvement in the induction process. Consistent with this finding, DEP stimulated phosphorylation of ERK1/2, JNK1, and p38 MAPKs with a distinct activation pattern. Overexpression of Fra-1 downregulated c-Jun and Nrf2 enhanced AP-1- and ARE-mediated reporter gene expression, respectively. In contrast, Fra-1 had the opposite effect on matrix metalloproteinase (MMP)-9 promoter activity. In particular, it bound to the functional AP-1 site of the MMP-9 promoter after DEP stimulation. Consistent with this result, DEP also markedly upregulated MMP-9 promoter activity. Collectively, these findings suggest that fra-1 induction by DEP may play a role in selectively regulating gene expression involved in alveolar epithelial cell injury and repair.
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PMID:DEP-induced fra-1 expression correlates with a distinct activation of AP-1-dependent gene transcription in the lung. 1456 43

The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity. To analyse the potential link between the ERK-MAPK pathway and AP-1 in colon cancer, in which RAS and BRAF mutations are frequent, we have studied the regulation of AP-1 in colon carcinoma cell lines. We show that c-JUN and FRA-1 expression is dependent on ERK activity and that different thresholds of ERK activity control the expression of FRA-1. A basal activity is required to induce transcription of the FRA-1 gene, but additional higher levels of activity stabilize FRA-1 against proteasome-dependent degradation. These results provide a clear-cut example that the magnitude of ERK signalling affects the cellular response. Although we find no contribution of FRA-1 towards cell proliferation of adherent tumour cells, the high levels of FRA-1 in cells where elevated ERK activity leads to protein stabilization provide survival signals for tumour cells removed from the extracellular matrix.
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PMID:Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. 1462 89

Aplidin is an antitumor drug that induces apoptosis and activates EGFR, Src, JNK and p38MAPK. Here, we show that Aplidin induces c-JUN, JUN B, JUN D, c-FOS, FRA-1 and FOS B genes of the activator-protein (AP)-1 family, and also p65/RELA, a major component of nuclear factor-kappa B (NF-kappaB). Concordantly, Aplidin increases AP-1 and NF-kappaB activity. c-FOS induction depends on EGFR, Src and JNK/p38MAPK. In contrast, induction of c-JUN does not require EGFR activity and p65/RELA induction is only partially dependent on these kinases. We used several genetically deficient cells to identify the critical target of Aplidin. Mouse embryo fibroblasts (MEFs) deficient for src, yes and fyn, and those lacking all p38MAPK isoforms displayed normal Aplidin sensitivity (IC50=12 nM). In contrast, MEFs lacking jnk1 and jnk2, which do not express any JNK isoform, were much less sensitive (IC50>500 nM). Furthermore, cells lacking c-jun or expressing a c-Jun protein in which JNK targets Ser(63/73) were mutated (c-JunAA) showed intermediate sensitivity (IC50=60 nM). Additionally, Aplidin has higher cytotoxic activity against proliferating than quiescent cells, which is reflected in higher JNK activation. We conclude that phosphorylation by JNK of c-Jun and additional substrate(s) is crucial for Aplidin activity.
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PMID:JNK activation is critical for Aplidin-induced apoptosis. 1512 39

The transcription factor AP-1 plays a central role in the transcriptional regulation of specific types of high-risk human papillomaviruses (HPVs) such as HPV16 and HPV18, which are etiologically associated with the development of cancer of the uterine cervix in women. In our study, we investigated the AP-1 binding activity and the expression pattern of different members of the AP-1 transcription factor family (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2) in different grades of cervical lesions starting from mild dysplasia to invasive cervical tumors, including normal control tissues, using specific antibodies raised against each of the AP-1 members. Results indicate that though AP-1 showed high binding activity and the majority of its members were highly expressed in tumor tissues, there is a distinct pattern of gradual increase of c-fos and a concomitant decrease of fra-1 expression that perfectly match the progression of cervical lesions. While c-fos is highly expressed in invasive cervical tumor, the expression of fra-1 becomes almost nil or absent, but the reverse is true in both controls and early precancerous lesions. These findings corroborate the results obtained in the cervical cancer cell line, HeLa. Interestingly, despite very low or absent AP-1 binding in normal as well as in premalignant lesions, AP-1 transcription and its binding activity was found to be very high in malignant tissues showing a preferential heterodimerization of c-fos with JunB instead of its canonical dimerization partner c-jun. Both in vivo and in vitro studies demonstrate that the overexpression of c-fos and downregulation of fra-1 expression as well as a change in the dimerization pattern of the AP-1 complex seem to play a crucial role during progression to malignancy. In a previous study, we demonstrated that a synthetic antioxidant, pyrrolidine dithiocarbamate (PDTC) can selectively downregulate HPV expression in human keratinocytes and cervical cancer cell lines. Since a redox regulatory pathway is involved in the expression of HPV that can be modulated by an antioxidant-induced reconstitution of the AP-1 transcription complex, we have used curcumin (diferuloylmethane), an active component of the perennial herb turmeric, which is a potent antioxidant and is well-known for its antiinflammatory and anticarcinogenic activity, to modulate the transcription of AP-1 and HPV. We demonstrate for the first time that curcumin can selectively downregulate HPV18 transcription as well as the AP-1 binding activity in HeLa cells. Most interestingly, curcumin can reverse the expression dynamics of c-fos and fra-1 in this tumorigenic cell line, mimicking the expression pattern observed in normal controls or precancerous lesions. Observation of curcumin-mediated complete downregulation of AP-1 binding activity and reversal of c-fos/fra-1 transcription to a normal state in tumorigenic HeLa cells represents a novel mechanism that can control transcription of pathogenic HPVs during keratinocyte differentiation and progression of cervical cancer. Our study thus provides a basis for developing a novel therapeutic approach to control pathogenic HPV infection by using potent antioxidative agents, such as curcumin.
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PMID:Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. 1551 44

Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
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PMID:Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. 1552 91

We describe cyclic hydrostatic pressure of 200/100 mmHg with a frequency of 85/min as a hemodynamically relevant pathological condition enforcing apoptosis in endothelial cells (EC) after 24 h of treatment. This went along with an increase of CD95 and CD95L surface expression, shedding of CD95L into the supernatant, cleavage of caspase-3 and caspase-8, and elevated JNK-2, c-Jun, and CD95L mRNA expression. Furthermore, increased DNA-binding activity of the AP-1 transcription factor family members FRA-1 and c-Jun was observed. This activation was reduced by inhibition of JNK, which subsequently prevented elevated CD95L mRNA expression. Caspase inhibitors and a CD95L-neutralizing antibody also reduced EC apoptosis. Most of the pressure-induced events were most prominent at 24 and 48 h. However, after 48 h, the CD95/CD95L expression pattern switched back to CD95-/CD95L+ and the specific death rate decreased. Cyclic pathological hydrostatic pressure is a novel type of stress to EC that renders them susceptible to CD95/CD95L-mediated autoapoptosis and/or paracrine apoptosis accompanied by upregulation of intracellular molecules known to trigger both apoptosis and survival.
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PMID:Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells. 1577 24


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