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)

Retinoic acid induces P19 mouse embryonal carcinoma cells to differentiate to endoderm and increases expression of the heterotrimeric G-protein subunits Galpha12 and Galpha13. Retinoic acid was found to induce differentiation and sustained activation of c-Jun amino-terminal kinase, but not of ERK1,2 or of p38 mitogen-activated protein kinases. Much like retinoic acid, expression of constitutively active forms of Galpha12 and Galpha13 induced differentiation and constitutive activation of c-Jun amino-terminal kinase. Expression of the dominant negative form of c-Jun amino-terminal kinase 1 blocked both the activation of c-Jun amino-terminal kinase and the induction of endodermal differentiation in the presence of retinoic acid. These data implicate c-Jun amino-terminal kinase as a downstream element of activation of Galpha12 or Galpha13 obligate for retinoic acid-induced differentiation.
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PMID:c-Jun amino-terminal kinase is regulated by Galpha12/Galpha13 and obligate for differentiation of P19 embryonal carcinoma cells by retinoic acid. 930 8

Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces the matrix metalloproteinases collagenase, 92-kD gelatinase, and stromelysin, which degrade skin connective tissue and may contribute to premature skin aging (photoaging). Pretreatment of skin with all-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism of tRA inhibition of UV induction of matrix metalloproteinases in human skin in vivo. Exposure of human skin in vivo to low doses of UV activated EGF receptors, the GTP-binding regulatory protein p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which bound to the c-Jun promoter and upregulated c-Jun gene expression. Elevated c-Jun, in association with constitutively expressed c-Fos, formed increased levels of transcription factor activator protein (AP) 1, which is required for transcription of matrix metalloproteinases. Pretreatment of human skin with tRA inhibited UV induction of c-Jun protein and, consequently, AP-1. c-Jun protein inhibition occurred via a posttranscriptional mechanism, since tRA did not inhibit UV induction of c-Jun mRNA. These data demonstrate, for the first time, activation of MAP kinase pathways in humans in vivo, and reveal a novel posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin.
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PMID:Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. 950 86

Expression of tissue factor (TF) by activated monocytes in several diseases leads to disseminated intravascular coagulation. Lipopolysaccharide (LPS)-induced monocyte TF expression is downregulated by the nuclear hormone all-trans retinoic acid (ATRA). In this study, we examined the mechanism by which ATRA inhibits monocyte TF expression. We show that ATRA selectively inhibited LPS induction of TF expression in human monocytes and monocytic THP-1 cells without affecting LPS induction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). Inhibition of TF expression occurred at the level of transcription as determined by nuclear run-on. ATRA did not significantly alter the binding or functional activity of the transcription factors c-Fos/c-Jun and c-Rel/p65, which are required for LPS induction of the TF promoter in monocytic cells. In contrast to the ATRA inhibition of the endogenous TF gene, LPS induction of the cloned TF promoter was not inhibited by ATRA in transiently transfected THP-1 cells. Our results demonstrate that ATRA selectively inhibited LPS-induced TF gene transcription in human monocytic cells by a mechanism that does not involve repression of AP-1- or NF-kappaB-mediated transcription.
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PMID:Retinoic acid selectively inhibits lipopolysaccharide induction of tissue factor gene expression in human monocytes. 953 96

To study the long-term effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the DNA-binding activity of nuclear transcription factors; a single dose of TCDD was injected intraperitoneally to male guinea pigs (1 microgram/kg i.p.). The animals were killed after 1, 2, 10, 20, 28, and 40 days, and DNA-binding activities in liver nuclear fraction were assessed through electrophoretic gel mobility shift assay (EMSA). As expected, the nuclear protein binding to dioxin or xenobiotic response element (DRE or XRE) increased as a result of TCDD's action (1-20 days). In addition, protein binding to 32P-labeled activator protein-1 (AP-1) response element (RE) (1-28 days) and activator protein-2 (AP-2) RE (1-28 days) were all increased by the action of TCDD. On the other hand, TCDD treatment significantly lowered the nuclear protein binding to both specific protein-1 (Sp-1) RE and c-MycRE at all time points (1-40 days). In the case of protein binding to 32P-labeled cAMP response element (CRE), we found two groups of binding bands being affected by TCDD. The intensity of the upper band group decreased, and that of the lower band group increased. As for AP-1 proteins, judging by the results of the Western blotting assay, the level of c-Fos increased while that of c-Jun decreased with TCDD treatment both at day 1 and 28. It is known that the rise in AP-1 and AP-2 activities often results in lowering certain cell differentiation signaling messengers in the nucleus. In agreement with this scenario, binding of C/EBP (CCAAT enhancer binding protein) to its response element site was found to be suppressed for 1 through 28 days. Among hormone receptors, TCDD treatment decreased the binding to retinoic acid RE but increased the binding to thyroid hormone RE.
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PMID:Effect of in vivo administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on DNA-binding activities of nuclear transcription factors in liver of guinea pigs. 958 Aug 71

In different experimental models, retinoid has been shown to stimulate or suppress mitogenesis in cultured cells. The mechanisms underlying this seemingly paradoxical activity remain only partially understood. We have examined the ability of all-trans retinoic acid (ATRA), as well as a number of synthetic retinoids, either alone or in the presence of a mitogenic stimulus (i.e., endothelin), to regulate DNA synthesis and cell replication in cultured rat aortic smooth muscle cells. ATRA alone stimulates [3H]thymidine incorporation (approximately twofold) and increases cell number (approximately twofold) in these cultures but suppresses [3H]thymidine incorporation and reduces cell number in cultures treated with endothelin. The reduction in endothelin-stimulated DNA synthesis correlates closely with the ability of ATRA to inhibit endothelin-stimulated extracellular signal-regulated kinase but not c-Jun NH2-terminal kinase activity. Activation of mitogenesis, seen in the presence of ATRA alone, was independent of extracellular signal-regulated kinase activation but correlated well with increased expression of cyclin D1 mRNA and protein. Concomitant activation of the cdk inhibitor p21 led to truncation of ATRA's mitogenic activity at higher doses of ligand. Collectively, these data indicate that the role of retinoids in the regulation of mitogenesis in vascular smooth muscle is complex. Under quiescent conditions they activate mitogenesis, while in the presence of growth stimulation, as is frequently seen with vasculopathic conditions, they suppress mitogenesis. It appears that independent circuitry is involved in signaling each of these effects.
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PMID:Retinoic acid uses divergent mechanisms to activate or suppress mitogenesis in rat aortic smooth muscle cells. 971 Apr 32

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (alpha, beta, gamma) and AP-1 (c-Jun and c-Fos) expression in the rat liver were examined by using Western blot analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5- and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RARalpha, -beta, and -gamma genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol.
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PMID:Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. 973 67

Ultraviolet radiation from the sun damages human skin, resulting in an old and wrinkled appearance. A substantial amount of circumstantial evidence indicates that photoaging results in part from alterations in the composition, organization, and structure of the collagenous extracellular matrix in the dermis. This paper reviews the authors' investigations into the molecular mechanisms by which ultraviolet irradiation damages the dermal extracellular matrix and provides evidence for prevention of this damage by all-trans retinoic acid in human skin in vivo. Based on experimental evidence a working model is proposed whereby ultraviolet irradiation activates growth factor and cytokine receptors on keratinocytes and dermal cells, resulting in downstream signal transduction through activation of MAP kinase pathways. These signaling pathways converge in the nucleus of cells to induce c-Jun, which heterodimerizes with constitutively expressed c-Fos to form activated complexes of the transcription factor AP-1. In the dermis and epidermis, AP-1 induces expression of matrix metalloproteinases collagenase, 92 kDa gelatinase, and stromelysin, which degrade collagen and other proteins that comprise the dermal extracellular matrix. It is hypothesized that dermal breakdown is followed by repair that, like all wound repair, is imperfect. Imperfect repair yields a deficit in the structural integrity of the dermis, a solar scar. Dermal degradation followed by imperfect repair is repeated with each intermittent exposure to ultraviolet irradiation, leading to accumulation of solar scarring, and ultimately visible photoaging. All-trans retinoic acid acts to inhibit induction of c-Jun protein by ultraviolet irradiation, thereby preventing increased matrix metalloproteinases and ensuing dermal damage.
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PMID:Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. 973 61

In the presence of retinoic acid (RA), the retinoid receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), are able to up-regulate transcription directly by binding to RA-responsive elements on the promoters of responsive genes. Liganded RARs and RXRs are also capable of down-regulating transcription, but, by contrast, this is an indirect effect, mediated by the interaction of these nuclear receptors not with DNA but the transcription factor activating protein-1 (AP-1). AP-1 is a dimeric complex of the protooncoproteins c-Jun and c-Fos and directly regulates transcription of genes important for cellular growth. Previous in vitro results have suggested that RARs can block AP-1 DNA binding. Using a mammalian two-hybrid system, we report here that human RARalpha (hRARalpha) can disrupt in a RA-dependent manner the homo- and heterodimerization properties of c-Jun and c-Fos. This inhibition of dimerization is cell specific, occurring only in those cells that exhibit RA-induced repression of AP-1 transcriptional activity. Furthermore, this mechanism appears to be specific for the RARs, since another potent inhibitor of AP-1 activity, the glucocorticoid receptor, does not affect AP-1 dimerization. Our data argue for a novel mechanism by which RARs can repress AP-1 DNA binding, in which liganded RARs are able to interfere with c-Jun/c-Jun homodimerization and c-Jun/c-Fos heterodimerization and, in this way, may prevent the formation of AP-1 complexes capable of DNA binding.
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PMID:Ligand-activated retinoic acid receptor inhibits AP-1 transactivation by disrupting c-Jun/c-Fos dimerization. 997 57

Solar UV radiation damages human skin, affecting skin tone and resiliency and leading to premature aging (photoaging), the symptoms of which include leathery texture, wrinkles, mottled pigmentation, laxity and sallowness. We propose that photoaging results largely from UV induction of matrix metalloproteinases (MMP) that degrade skin collagen. We find that pretreatment of human skin with all-trans retinoic acid (tRA) inhibits UV induction of MMP, suggesting that tRA can protect against UV-induced collagen destruction and may therefore be able to lessen the effects of photoaging. The tRA prevents UV-induced accumulation of c-Jun protein, which is required for MMP gene expression. Activation of c-Jun transcriptional activity requires N-terminal phosphorylation. The majority of c-Jun in human skin in vivo is N-terminal phosphorylated. Topically applied tRA does not inhibit N-terminal phosphorylation by UV-induced c-Jun kinase activity in human skin. The tRA likely acts to reduce UV induction of c-Jun protein by stimulating its breakdown through the ubiquitin-proteasome pathway.
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PMID:Molecular mechanisms of photoaging in human skin in vivo and their prevention by all-trans retinoic acid. 1004 11

Chronic and excessive ethanol consumption is associated with cellular proliferation, fibrosis, cirrhosis, and cancer of the liver. The critical event in early alcohol-induced hepatic injury is an alcohol-induced activation (cell proliferation and increased fibrogenesis) of hepatic stellate cells. However, the mechanisms by which alcohol causes proliferative activation in hepatic stellate cells have not been identified. An important characteristic of alcohol-induced injury is impaired vitamin A nutritional status. The demonstration that retinoic acid is the most physiologically active derivative of vitamin A and the discovery of retinoic acid receptors provide a mechanistic basis for understanding the actions of vitamin A and alcohol on hepatic cell proliferation. Recent studies have demonstrated that chronic alcohol intake can reduce hepatic retinoic acid concentrations, diminish retinoid signaling, and enhance activator protein-1 (AP-1 (c-Jun and c-Fos)) expression in rat liver. These are the possible biochemical and molecular mechanisms whereby ethanol ingestion results in hepatic stellate cell proliferative activation and hepatic fibrogenesis.
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PMID:Chronic alcohol intake interferes with retinoid metabolism and signaling. 1007 3


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