UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid (RA) causes differentiation of mouse F9 embryonic carcinoma cell line into primitive and parietal (with dibutiril-cAMP) endoderm. The role of AP-1 transcription factor during RA-induced differentiation was studied in F9 cell line. It was shown that differentiated cells acquired protein complexes, which are specifically bound to well characterized AP-1 32P-labeled binding sites from collagenase (Col-AP-1) and c-jun (Jun2-AP-1) promoters. These complexes contain c-Fos/c-Jun with Col-AP-1 site and c-Jun/ATF-2 with Jun2-AP-1 site as revealed by supershift analysis. DNA-binding activity of these complexes is high in parietal endoderm but low-detectable in undifferentiated cells. DNA-binding activity of AP-1 transcription factor correlates with increased expression of c-fos and c-jun genes. RT-PCR analysis showed an increase in steady-state level of c-fos and c-jun gene transcription at the stage of parietal endoderm (terminally differentiated F9 cells). Transcription of immediate early c-fos and c-jun genes and DNA-binding activity of c-Fos/c-Jun complex are serum dependent. The rate of c-fos and c-jun gene transcription and DNA-binding activity of c-Fos/c-Jun complex decreased in serum-starved cells, but was rapidly induced upon stimulation with serum. Undifferentiated F9 cells contain a very low level of c-fos mRNA, with may be a consequence of repressive chromatin structure in promoter region. Histone deacetylase (HDAC) activity is necessary to restrict expression of specific number of genes, also HDAC inhibitors are well known inductors of differentiation and anticancer agents. Frow cytometry analysis showed a decreased rate of proliferation of F9 cells after their incubation with HDAC inhibitors, sodium butirate and trichostatin A. Also, these ihibitors induced the transcription of c-fos gene. So, we conclude that HDAC activity may be necessary to sustain a high proliferative rate of undifferentiated F9 cells.
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PMID:[Transcription of c-fos gene and DNA binding activity of transcription factor AP-1 increase upon differentiation of mouse F9 teratocarcinoma cells]. 1574 38

Ultraviolet (UV) irradiation regulates UV-responsive genes, including matrix metalloproteinases (MMPs). Moreover, UV-induced MMPs cause connective tissue damage and the skin to become wrinkled and aged. Here, we investigated the effect of eicosapentaenoic acid (EPA), a dietary omega-3 fatty acid, on UV-induced MMP-1 expression in human dermal fibroblasts (HDFs). We found that UV radiation increases MMP-1 expression and that this is mediated by p44 and p42 MAP kinase (ERK) and Jun-N-terminal kinase (JNK) activation but not by p38 activation. Pretreatment of HDFs with EPA inhibited UV-induced MMP-1 expression in a dose-dependent manner and also inhibited the UV-induced activation of ERK and JNK by inhibiting ERK kinase (MEK1) and SAPK/ERK kinase 1 (SEK1) activation, respectively. Moreover, inhibition of ERK and JNK by EPA resulted in the decrease of c-Fos expression and c-Jun phosphorylation/expression induced by UV, respectively, which led to the inhibition of UV-induced activator protein-1 DNA binding activity. This inhibitory effect of EPA on MMP-1 was not mediated by an antioxidant effect. We also found that EPA inhibited 12-O-tetradecanoylphorbol-13-acetate- or tumor necrosis factor-alpha-induced MMP-1 expression in HDFs and UV-induced MMP-1 expression in HaCaT cells. In conclusion, our results demonstrate that EPA can inhibit UV-induced MMP-1 expression by inhibiting the MEK1/ERK/c-Fos and SEK1/JNK/c-Jun pathways. Therefore, EPA is a potential agent for the prevention and treatment of skin aging.
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PMID:Eicosapentaenoic acid inhibits UV-induced MMP-1 expression in human dermal fibroblasts. 1593 May 17

Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.
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PMID:Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2. 3190 Mar 76

Interleukin (IL)-1beta induces the expression of matrix metalloproteinases (MMPs) implicated in cartilage resorption and joint degradation in osteoarthritis (OA). Pomegranate fruit extract (PFE) was recently shown to exert anti-inflammatory effects in different disease models. However, no studies have been undertaken to investigate whether PFE constituents protect articular cartilage. In the present studies, OA chondrocytes or cartilage explants were pretreated with PFE and then stimulated with IL-1beta at different time points in vitro. The amounts of proteoglycan released were measured by a colorimetric assay. The expression of MMPs, phosphorylation of the inhibitor of kappaBalpha (IkappaBalpha) and mitogen-activated protein kinases (MAPKs) was determined by Western immunoblotting. Expression of mRNA was quantified by real-time PCR. MAPK enzyme activity was assayed by in vitro kinase assay. Activation of nuclear factor-kappaB (NF-kappaB) was determined by electrophoretic mobility shift assay. PFE inhibited the IL-1beta-induced proteoglycan breakdown in cartilage explants in vitro. At the cellular level, PFE (6.25-25 mg/L) inhibited the IL-1beta-induced expression of MMP-1, -3, and -13 protein in the medium (P < 0.05) and this was associated with the inhibition of mRNA expression. IL-1beta-induced phosphorylation of p38-MAPK, but not that of c-Jun-N-terminal kinase or extracellular regulated kinase, was most susceptible to inhibition by low doses of PFE, and the addition of PFE blocked the activity of p38-MAPK in a kinase activity assay. PFE also inhibited the IL-1beta-induced phosphorylation of IkappaBalpha and the DNA binding activity of the transcription factor NF-kappaB in OA chondrocytes. Taken together, these novel results indicate that PFE or compounds derived from it may inhibit cartilage degradation in OA and may also be a useful nutritive supplement for maintaining joint integrity and function.
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PMID:Punica granatum L. extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. 1614 Aug 82

Solar UV light comprises UVB wavelengths (290-320 nm) and UVA wavelengths (320-400 nm). UVB radiation reaches the epidermis and, to a lesser extent, the upper part of the dermis, while UVA radiation penetrates more deeply into human skin. Existing studies have demonstrated that UV-irradiated epidermal keratinocytes release cytokines that indirectly promote MMP-1 production in dermal fibroblasts. In this study, we first investigated the effect of IL-1 on MAPK activity, c-Jun and c-Fos mRNA expression, and MMP-1 and MMP-2 production in UVA-irradiated human dermal fibroblasts. The results showed that UVA irradiation dose-dependently increased MMP-1 but not MMP-2 production in human skin fibroblasts. IL-1alpha and IL-1beta promoted MMP-1 but not MMP-2 production in UVA-irradiated fibroblasts. Both IL-1alpha and IL-1beta activated MAP kinase, significantly elevating c-Jun and c-Fos mRNA expression. We then investigated the indirect effect of UVB-irradiated keratinocyte culture medium on MMP-1 production in UVA-irradiated primary cultured human dermal fibroblasts and the effect of IL-1Ra. The results showed that cell culture medium from UVB-irradiated keratinocytes increased MMP-1 production in UVA-irradiated fibroblasts, and IL-1Ra dose-dependently inhibited MMP-1 production. IL-1Ra dose-dependently inhibited c-Jun mRNA expression of fibroblasts with no significant effect on c-Fos mRNA expression. These results demonstrate that UVB-irradiated keratinocytes promoted MMP-1 production in UVA-irradiated fibroblasts in a paracrine manner while IL-1Ra reduced MMP-1 production through inhibiting c-Jun mRNA expression. Collectively, our data suggest that IL-1 plays an important role in the dermal collagen degradation associated with UV-induced premature aging of the skin and IL-1Ra may be applied for the prevention and treatment of photoaging.
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PMID:IL-1 receptor antagonist attenuates MAP kinase/AP-1 activation and MMP1 expression in UVA-irradiated human fibroblasts induced by culture medium from UVB-irradiated human skin keratinocytes. 1627 95

Tissue fibrosis results when dysregulation of extracellular matrix (ECM) turnover favors deposition of collagen and other ECM proteins over degradation. Fibrosis may then lead to organ dysfunction and pathology as observed in systemic sclerosis (SSc). In the present study, we investigated the antifibrotic properties of proteasome blockade. A dose- and time-dependent reduction in type-I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) production was observed in normal fibroblasts exposed to proteasome inhibitors (PI). In the same culture conditions, metalloproteinase-1 (MMP-1) protein and the collagenolytic activity on type I collagen was increased. The steady-state mRNA levels of COL1A1, TIMP-1, and MMP-1 paralleled protein levels. These effects were dominant over the profibrotic properties of TGF-beta and were observed with fibroblasts generated from normal and SSc skin. PI decreased type I collagen mRNA levels with kinetics similar to those observed with DRB, a specific RNA polymerase II inhibitor, thus indicating transcriptional inhibition. Of interest, PI induced c-Jun phosphorylation and c-Jun nuclear accumulation. The specific N-terminal Jun-kinase inhibitor SP-600125 selectively abrogated c-Jun phosphorylation and, in a dose-dependent fashion, the up-regulated synthesis of MMP-1 induced by PI. Finally, PI did not affect fibroblast viability. Thus, the coordinated down-regulation of collagen and TIMP-1 and up-regulation of MMP-1 renders proteasome blockade an attractive strategy for treating conditions as SSc, characterized by excessive fibrosis.
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PMID:Proteasome blockade exerts an antifibrotic activity by coordinately down-regulating type I collagen and tissue inhibitor of metalloproteinase-1 and up-regulating metalloproteinase-1 production in human dermal fibroblasts. 1641 Mar 44

UV-induced matrix metalloproteinases (MMPs) cause connective tissue damage and the skin to become wrinkled and aged. Here, we investigated the effect of 2',4',7-trihydroxyisoflavone (THF) on UV-induced MMP-1 expression in human skin fibroblasts (HSFs). We found that UV irradiation increases MMP-1 expression and that this is mediated by ERK and JNK activation, but not by p38 activation. Pretreatment of HSFs with 2',4',7-THF inhibited UV-induced MMP-1 expression in a dose-dependent manner, and also inhibited the UV-induced activations of ERK and JNK by inhibiting MEK1 and SEK1 activation, respectively. Moreover, inhibitions of ERK and JNK by 2',4',7-THF resulted in the decrease of c-Fos expression and c-Jun phosphorylation/expression induced by UV, respectively, which led to the inhibition of UV-induced AP-1 DNA binding activity. This inhibitory effect of 2',4',7-THF on MMP-1 was not mediated by an antioxidant effect. In conclusion, our results demonstrate that 2',4',7-THF can inhibit UV-induced MMP-1 expression by inhibiting the MEK1/ERK/c-Fos and SEK1/JNK/c-Jun pathways. Therefore, 2',4',7-THF is a potential agent for the prevention and treatment of skin aging.
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PMID:The effect of 2',4',7-trihydroxyisoflavone on ultraviolet-induced matrix metalloproteinases-1 expression in human skin fibroblasts. 1677 40

Overexpression of cyclooxygenase-2 (COX-2) is regarded as a causative factor in the onset of tumorigenesis of the breast. In this study, we investigated the effects of conjugated linoleic acid (CLA) on COX-2 transcription in MCF-7 breast cancer cells. Results of transient transfection studies revealed that treatment with a CLA mix or selected isomers (c9, t11-CLA; t10, c12-CLA) at concentrations ranging from 20 to 80 micromol/L, attenuated COX-2 transcription induced by the proinflammatory agent 12-O-tetradecanoylphorbol-13-acetate (TPA). In addition, the CLA mix inhibited TPA-induced activity of the collagenase-1 promoter. Using electrophoretic mobility shift assays, we found that the CLA mix reduced TPA-induced recruitment of nuclear proteins to a cAMP response element (CRE) in the COX-2 promoter and a consensus TPA-responsive element (TRE) in the collagenase-1 promoter. Both CRE and TRE are binding sites for activator protein-1 (AP-1). Binding studies revealed that the t10, c12-CLA isomer was more effective than the CLA mix or c9, t11-CLA in reducing binding of cJun to either the COX-2 CRE or collagenase-1 TRE, whereas linoleic acid increased binding to both elements. Overexpression of the AP-1 member, c-Jun, reversed the inhibitory effects of the CLA mix on COX-2 transcription, and restored binding of nuclear proteins to the CRE and TRE. Collectively, these results suggest that CLA represses AP-1-mediated activation of COX-2 transcription.
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PMID:Conjugated linoleic acid attenuates cyclooxygenase-2 transcriptional activity via an anti-AP-1 mechanism in MCF-7 breast cancer cells. 1642 22

Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent.
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PMID:Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo. 1646 81

Reactive oxygen species have been shown to play an important role in the regulation of distinct signaling cascades, many of which act upon the production of matrix metalloproteinases (MMP). Using a series of redox-engineered cell lines we have previously demonstrated that MMP-1 expression is sensitive to the alterations in the steady state production of H2O2 (Ranganathan, A. C., Nelson, K. K., Rodriguez, A. M., Kim, K. H., Tower, G. B., Rutter, J. L., Brinckerhoff, C. E., Epstein, C. J., Huang, T. T., Jeffrey, J. J., and Melendez, J. A. (2001) J. Biol. Chem. 276, 14264-14270). In the present study, we investigate the molecular mechanisms involved in the H2O2-mediated induction of MMP-1. Mutational analysis of an MMP-1 promoter indicates that both the single nucleotide polymorphism creating an Ets binding site at -1607 and a proximal AP-1 site at -1602 are required for maximal H2O2-dependent transcription. The redox-sensitive MMP-1 protein expression requires activation of both ERK1/2 and JNK pathways. Importantly, JNK signaling is largely responsible for the H2O2 sensitivity of the MMP-1 promoter, whereas ERK1/2 contributes to both its basal and H2O2 dependence. H2O2 control of Ets-1 expression was ERK1/2-dependent whereas that of c-Jun requires both ERK1/2 and JNK signaling. Chromatin immunoprecipitation assays indicate that binding of the histone acetyltransferase, p300, and the transcription factors Ets-1 and c-Jun to the MMP-1 promoter is redox sensitive. The redox sensitivity of MMP-1 expression is also associated with an increase in the abundance of oxidatively inactivated protein-tyrosine phosphatases. Targeted cytosolic or mitochondrial scavenging of H2O2 prevented all of the aforementioned signals. These studies provide substantial insight into the mechanisms underlying the redox-dependent control of MMP-1 and may lead to the development of novel targeted antioxidant-based inhibitory therapies for controlling MMP-1 expression during degenerative disease processes.
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PMID:Redox-dependent matrix metalloproteinase-1 expression is regulated by JNK through Ets and AP-1 promoter motifs. 1656 38

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