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PubMed1998

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.

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.

Activating Transcription Factor 2↗

PubMed1987

Homology between the DNA-binding domain of the GCN4 regulatory protein of yeast and the carboxyl-terminal region of a protein coded for by the oncogene jun.

The product of the recently described oncogene jun shows significant amino acid sequence homology with the GCN4 yeast transcriptional activator protein. The similarity is restricted to the 66 carboxyl-terminal amino acids, thought to be the DNA-binding domain of the GCN4 protein. In these alpha-helix-permissive regions of the jun and GCN4 products there is also a lesser but still significant amino acid resemblance to the fos protein and a marginal degree of similarity to myc proteins. The amino acid sequence homology between GCN4 and jun gene products suggests that the jun protein may bind to DNA in a sequence-specific way and exert a regulatory function.

Amino Acid Sequence↗

PubMed1992

The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases.

Exposure of mammalian cells to DNA-damaging agents induces the ultraviolet (UV) response, involving transcription factor AP-1, composed of Jun and Fos proteins. We investigated the mechanism by which UV irradiation induces the c-jun gene. The earliest detectable step was activation of Src tyrosine kinases, followed by activation of Ha-Ras and Raf-1. The response to UV was blocked by tyrosine kinase inhibitors and dominant negative mutants of v-src, Ha-ras, and raf-1. This signaling cascade leads to increased phosphorylation of c-Jun on two serine residues that potentiate its activity. These results strongly suggest that the UV response is initiated at or near the plasma membrane rather than the nucleus. The response may be elicited by oxidative stress, because it is inhibited by elevation of intracellular glutathione. Using tyrosine kinase inhibitors, we demonstrate that the UV response has a protective function.

Cell Membrane↗

PubMed1992

Genotoxic-stress-response genes and growth-arrest genes. gadd, MyD, and other genes induced by treatments eliciting growth arrest.

As discussed throughout this paper, many mammalian DDI genes are associated with growth responses, including both positive responses to growth stimulation and negative responses involving transient growth arrest and terminal differentiation. It is interesting that several immediate-early genes encoding transcription factors, the jun genes, are DDI, are induced by terminal differentiation, and also are associated with positive growth responses. In negative growth-response genes, their control is complex and almost certainly involves multiple regulatory mechanisms. The role of growth-arrest genes after exposure to DNA-damaging agents is currently not known, but as growth arrest can have a protective effect on cells exposed to DNA-damaging agents in both bacteria and eukaryotes, some protective role(s) for the gadd genes may exist. Whatever the roles are for the individual gadd genes, the response of the gadd genes to DNA-damaging agents and other growth-arrest signals has been highly conserved during mammalian evolution, and it is likely that this stress response, as reflected by induction of one or more gadd genes, is present in most or perhaps all mammalian cells. Our findings that the gadd group overlaps with another group of growth-arrest genes, the MyD, indicate that these two groups combined define a new class of genes whose protein products are likely to play a role in cell growth cessation.

Aging↗

PubMed1994

Intracellular glutathione levels regulate Fos/Jun induction and activation of glutathione S-transferase gene expression.

Induction of glutathione S-transferase Ya and NAD(P)H:quinone reductase gene expression by a variety of chemical agents is mediated by regulatory elements, EpRE and ARE, composed of two adjacent AP-1-like binding sites and activated by Fos/Jun heterodimeric complex (AP-1). Recent studies show that chemical induction of glutathione S transferase Ya and quinone reductase gene expression is associated with an induction of c-fos and c-jun gene expression and AP-1 binding activity. In this report we present evidence that the AP-1 binding activity and the expression of chloramphenicol acetyltransferase activity from an EpRE Ya-cat gene construct are induced by an increase in intracellular oxidant levels. We observe that lowering the glutathione levels with buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, or diamide, a thiol-oxidizing agent, stimulates both basal and chemical-inducible expression of chloramphenicol acetyltransferase activity from EpRE Ya-cat and the AP-1 binding activity. Furthermore, we observe that the induction of these activities by a variety of chemical agents is inhibited by thiol compounds N-acetylcysteine and glutathione. These findings suggest that diverse chemicals that induce the AP-1 complex, leading to the AP-1-mediated transcriptional activation of glutathione S-transferase Ya gene expression, may act through a common mechanism involving the production of reactive oxygen species and depletion of reduced glutathione.

Buthionine Sulfoximine↗

PubMed1999

Selective activation in the MAPK pathway by Hg(II) in precision-cut rabbit renal cortical slices.

The kidneys are the primary organ for the accumulation and toxicity of inorganic mercury. In these studies the molecular response of precision-cut rabbit renal cortical slices to low levels of inorganic mercury was examined. Cortical slices (275 microm) were obtained from 1.0 kg NZW rabbits and exposed to mercuric chloride [Hg(II)] at concentrations of 0.01-10 microM for 2-8 h. Overt cytotoxicity, as assessed by intracellular K(+) levels, was not observed following exposure to these concentrations of Hg(II). However, an induction of heme-oxygenase-1 (Hsp32) was seen following a 2-h challenge to Hg(II). A dose-dependent induction of the DNA binding activity of the AP-1 transcription factor after 4 h of Hg(II) exposure correlated with a dose-dependent enhancement of c-jun gene expression following 2 h of Hg(II) exposure. Additionally, an increase in phosphorylated c-Jun NH(2)-terminal protein kinase (JNK) was observed following 2 h of Hg(II) exposure. These results suggest activation of the mitogen-activated protein (MAP) signal transduction pathway, specifically the c-Jun NH(2)-terminal protein kinase (JNK) pathway. No changes were observed, however, in the DNA binding activity of ATF2 and Elk-1, transcription factors involved in both the JNK and p38 pathways of MAP signal transduction, nor in the gene expression of c-myc. This selectivity of alterations in molecular signaling suggests an acute response in signal transduction, specifically activation of the JNK pathway in renal tissue following exposure to nanomolar concentrations of Hg(II).

Activating Transcription Factor 2↗

PubMed1996

The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase.

Trivalent arsenic (As3+) is highly carcinogenic, but devoid of known mutagenic activity. Therefore, it is likely to act as a tumor promoter. To understand the molecular basis for the tumor-promoting activity of As3+, we examined its effect on transcription factor AP-1, whose activity is stimulated by several other tumor promoters. We found that As3+, but not As5+, which is toxic but not carcinogenic, is a potent stimulator of AP-1 transcriptional activity and an efficient inducer of c-fos and c-jun gene expression. Induction of c-jun and c-fos transcription by As3+ correlates with activation of Jun kinases (JNKs) and p38/Mpk2, which phosphorylate transcription factors that activate these immediate early genes. No effect on ERK activity was observed. As5+, on the other hand, had a negligible effect on JNK or p38/Mpk2 activity. Biochemical analysis and co-transfection experiments strongly suggest that the primary mechanism by which As3+ stimulates JNK activity involves the inhibition of a constitutive dual-specificity JNK phosphatase. This phosphatase activity appears to be responsible for maintaining low basal JNK activity in non-stimulated cells and its inhibition may lead to tumor promotion through induction of proto-oncogenes such as c-jun and c-fos, and stimulation of AP-1 activity. The same phosphatase may also regulate p38/Mpk2 activity.

Arsenites↗

PubMed1995

Okadaic acid increases nerve growth factor secretion, mRNA stability, and gene transcription in primary cultures of cortical astrocytes.

Neonatal rat cortical astrocytes in primary culture synthesize and secrete nerve growth factor (NGF) in response to cytokines, growth factors, and activators of protein kinases. To further implicate a protein phosphorylation mechanism in the regulation of NGF expression, astrocytes were treated with okadaic acid and calyculin A, inhibitors of phosphoprotein phosphatases 1 and 2A. Okadaic acid dramatically increased both NGF mRNA content (50-fold) and NGF secretion (100-fold) in astrocytes, while calyculin A, which has a spectrum of phosphatase inhibitory activity different from okadaic acid, failed to augment NGF expression. The increased mRNA accumulation was due mainly to an increase (4-fold) in the half-life of the NGF mRNA following 9 or 24 h of treatment. Nuclear run-on assays indicated that okadaic acid also activated NGF gene transcription, which was preceded by an induction of c-fos and c-jun gene transcription. The induction of NGF expression by okadaic acid appeared independent from protein kinase C activity because down-regulating protein kinase C activity failed to decrease the okadaic acid stimulation. In contrast, interleukin-1 beta acted synergistically with okadaic acid to stimulate NGF secretion. The results indicate that okadaic acid profoundly stimulates NGF expression in astrocytes mainly by enhancing NGF mRNA stability and suggest important roles for phosphoprotein phosphatases in regulating NGF production.

Animals↗

PubMed1996

Ethanol exposure increases expression of c-jun and junD in human neuroblastoma cells.

The aim of this study was to investigate the effect of ethanol exposure on the expression of fos and jun genes. Exposure of human neuroblastoma SH-SY5Y cells to ethanol for 2-4 days caused a dose-dependent increase in c-jun and junD mRNA levels, whereas mRNAs for c-fos, fosB and junB were not detectable in control or ethanol-treated cells. Four days of ethanol exposure also enhanced the AP-1 binding activity. Experiments with actinomycin D demonstrated that ethanol did not influence the degradation of c-jun and junD mRNAs. These results demonstrate that long-term exposure to ethanol increases c-jun and junD expression. This effect may be one of the mechanisms through which ethanol influences the gene regulatory system in neuronal cells.

Cell Line↗

PubMed1994

Antisense c-jun overcomes a differentiation block in a murine erythroleukemia cell line.

We have studied the expression of the c-jun gene during dimethyl-sulfoxide (DMSO) induced differentiation of Friend erythroleukemia (F-MEL) cells. No expression of c-jun was detected in a differentiation-competent F-MEL cell line (745A) either before or after treatment with DMSO. By contrast, c-jun expression was constitutive in a F-MEL cell line (TFP10) resistant to DMSO-induced differentiation and increased with DMSO. We have investigated the possible role of c-jun in conferring this resistance by stably transfecting either sense or antisense c-jun constructs into both differentiation-sensitive 745A and defective TFP10 cell lines. Inhibition of c-jun expression by antisense transcripts in the TFP10 cells restored their ability to undergo erythroid differentiation when exposed to DMSO while expression of junB or junD antisense vectors failed to do so. In addition, c-jun overexpression in the 745A cells resulted in decreased DMSO-induced differentiation. These results indicate a correlation between the level of c-jun expression and the ability of F-MEL cells to undergo DMSO-induced differentiation and suggest that c-Jun may be an important negative regulator in this process.

Animals↗

PubMed1997

Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation.

For cells of the innate immune system to mount a host defence response to infection, they must recognize products of microbial pathogens such as lipopolysaccharide (LPS), the endotoxin secreted by Gram-negative bacteria. These cellular responses require intracellular signalling pathways, such as the four MAP kinase (MAPK) pathways. In mammalian cells the MAPK p38 is thought to play an important role in the regulation of cellular responses during infection through its effects on the expression of proinflammatory molecules. One means of understanding the role of p38 in these responses is to identify proteins with functions regulated by p38-catalysed phosphorylation. Here we demonstrate a link between the p38 pathway and a member of the myocyte-enhancer factor 2 (MEF2) group of transcription factors. We found that in monocytic cells, LPS increases the transactivation activity of MEF2C through p38-catalysed phosphorylation. One consequence of MEF2C activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-Jun protein consumed during infection.

Binding Sites↗

PubMed1999

Activity and expression of JNK1, p38 and ERK kinases, c-Jun N-terminal phosphorylation, and c-jun promoter binding in the adult rat brain following kainate-induced seizures.

The activity and/or expression of the mitogen-activated protein kinases c-Jun N-terminal kinase 1, p38 and extracellular signal-regulated kinases 1/2, as well as their substrates, the transcription factors c-Jun and activating transcription factor-2, were examined following systemic application of kainate in the cortex and hippocampus of the adult rat brain. The protein expression levels of all three mitogen-activated protein kinases remained constant during the observation period. Unexpectedly, c-Jun N-terminal kinase 1 was the only mitogen-activated protein kinase activated in this model of excitotoxicity, its activity raised from between 1 and 3 h moderate basal to maximal levels between 6 and 12 h. In contradistinction, activity of extracellular signal-regulated kinases 1/2 fell from their substantial basal levels and did not recover; activity of p38 was characterized by a high basal level that almost entirely disappeared and did not return to basal levels even 10 days after kainate application. c-Jun protein was rapidly expressed, with a maximum after 3 h and a slow decline after 12 h. Supershift assays revealed that, during the early induction phase of the c-jun gene, the proximal activator protein-1 (jun1) site of the c-jun promoter was mainly occupied by the constitutively expressed activating transcription factor-2, whereas the late induction correlated with the predominant binding of c-Jun and, to a lesser extent, activating transcription factor-2 to the distal activator protein-1 (jun2) site. The time-course of the N-terminal phosphorylation of c-Jun as determined by immunocytochemistry paralleled the activity of c-Jun N-terminal kinase 1 and showed a compartment-specific regulation between 3 and 12 h. A second set of supershift experiments demonstrated that c-Jun, but not activating transcription factor 2, bound to activator protein-1 sites in the promoter of substance P and collagenase genes, but not of the cyclo-oxygenase-2 gene. Our results demonstrate that activation of c-Jun N-terminal kinase 1, phosphorylation of c-Jun and selective occupation of the c-jun promoter by activating transcription factor-2 or c-Jun are part of the neuronal response following excitotoxicity that is considered as the mechanism for neuronal apoptosis in vivo. Some of these findings differ substantially from in vitro experiments and underline the necessity to analyse the neuronal stress pathways in the adult brain.

Animals↗

PubMed1999

Selective loss of PMA-stimulated expression of matrix metalloproteinase 1 in HaCaT keratinocytes is correlated with the inability to induce mitogen-activated protein family kinases.

Many cell types, including fibroblasts and primary keratinocytes, increase matrix metalloproteinase 1 (MMP-1) production in response to agonists such as growth factors and phorbol esters. However, the spontaneously transformed human keratinocyte cell line HaCaT, although it increases MMP-1 production in response to epidermal growth factor (EGF), does not respond similarly to stimulation with PMA. This phenomenon occurs even though HaCaT cells remain proliferatively responsive to both agonists, suggesting a HaCaT-specific defect in a PMA-mediated signal transduction pathway. Using an inside-out approach to elucidate the source of this defect, we found that EGF, but not PMA, stimulated MMP-1 promoter activity in transiently transfected HaCaT keratinocytes. In addition, an assessment of fibroblast and HaCaT c-fos and c-jun gene expression after exposure to EGF and PMA showed that although both agonists increased the expression of c-fos and c-jun mRNA in fibroblasts, only EGF did so in HaCaT keratinocytes. Finally, we looked at the activation of mitogen-activated protein (MAP) family kinases after stimulation with EGF or PMA and found that both agonists increased the phosphorylation and activation of fibroblast extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but only EGF activated the same kinase activities in HaCaT cells. Further, the EGF-mediated increase in MMP-1 gene expression was inhibited by the MAP kinase/ERK kinase (MEK)-specific inhibitor PD98059 and the p38 kinase-specific inhibitor SB203580. Our evidence indicates that although HaCaT MAP kinases are functional, they are not properly regulated in response to the activation of protein kinase C, and that the defect that bars HaCaT MMP-1 expression in response to stimulation with PMA lies before MAP kinase activation.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1986

Two new retroviral onc genes, sea and jun.

Avian leukemia virus S13 induces erythroblastosis, granulocytic leukemia, fibrosarcoma, anemia, and endothelial neoplasia. It transforms chick embryo fibroblasts and primitive erythroid cells in culture and is defective in replication. Its onc gene, sea, is expressed as transformation specific env-sea fusion glycoprotein of 155 kDa. Gp155 is proteolytically processed into gp85env and gp70env-sea. The latter shows tyrosine specific protein kinase activity. Avian sarcoma virus 17 induces fibrosarcoma and transforms chick embryo fibroblasts in culture. Its cell derived onc gene, jun, is not related to known onc genes and appears to be expressed as a gag-jun fusion protein of 55 kDa. The amino acid sequence of jun shows homology in its C-terminal region to the C-terminal DNA binding region of the yeast regulatory protein GCN4, suggesting that the jun protein may bind to DNA.

Amino Acid Sequence↗

PubMed1992

JunB does not inhibit the induction of c-Jun during the retinoic acid induced differentiation of F9 cells.

JunB, a member of the jun gene family of transcription factors, is distinguished from c-Jun by its differential activity on certain arrangements of promoter regulatory elements and the ability of JunB to inhibit the action of cJun in both transforming and trans-activating assays. We have tested the potential negative regulatory role of JunB during the retinoic acid induced differentiation of F9 murine embryonal carcinoma cells. Constitutive expression of high levels of JunB in F9 cells failed to inhibit the differentiation dependent induction of c-Jun or the coincident expression of differentiation markers keratin 8 and 18, tissue plasminogen activator, and laminin B1. Among these marker genes, keratin 18, has been shown to contain an AP-1 binding site, TGA(C/G)TCA, which is essential for high level, differentiation dependent expression and which is transactivated by Jun and Fos proteins. These results suggest that JunB does not play a major negative or positive regulatory role during the retinoic acid induced differentiation of F9 cells.

Base Sequence↗

PubMed1998

The transcription-repair coupling factor CSA is required for efficient repair only during the elongation stages of RNA polymerase II transcription.

The known nucleotide excision repair (NER) defects of xeroderma pigmentosum (XP) and Cockayne syndrome (CS) cells can be exploited to analyze mechanisms of repair of UV-induced cyclobutane pyrimidine dimers (CPDs) at nucleotide (nt.) resolution. The two gene products of the CS complementation groups (CSA and CSB) have been implicated in the preferential repair of the transcribed strand of human genes. We had previously described very efficient repair of CPDs at sequences near the transcription initiation site of the human JUN gene in normal fibroblasts. Here, we have analyzed repair in a CSA fibroblast strain. CSA cells exhibited rapid repair near the transcription initiation site (positions -45 to +15) but were deficient in repair of sequences on the transcribed strand beginning around nt. +20. There was also no strand-selective repair of sequences further downstream of the start site (+260 to +450). The results suggest that the transcription-repair coupling factor (TRCF) CSA is required for efficient repair only during the elongation stages of RNA polymerase II transcription. We also discuss possible mechanisms of differential repair observed near the transcription initiation site in XP and CS cells and conclude that these in vivo repair data support some recent models obtained from nucleotide excision repair experiments in vitro.

Cell Line↗

PubMed1996

[Ceramide: a lipid mediator of apoptotic signal transduction].

Ceramide, the backbone of sphingolipids, is now recognized as an intracellular signal mediator of various cellular responses including cell differentiation and apoptosis. Tumor necrosis factor-alpha, anti-Fas antibody, anticancer drugs, radiation or heat shock induce apoptosis through generation of ceramide by activation of sphingomyelinase or ceramide synthase. The mechanism by which ceramide mediates apoptosis is unclear. We have found that ceramide induces the transcription of c-jun gene and increases the DNA binding activity of transcription factor AP-1 in human myelogenous leukemia HL-60 cells, and that activation of c-jun/AP-1 by ceramide(presumably through activation of Jun N-terminal kinase/stress-activated protein kinase) may be involved in the signaling pathway leading to apoptosis.

Apoptosis↗

PubMed1995

Pronounced activation of protein kinase C, ornithine decarboxylase and c-jun proto-oncogene by paraquat-generated active oxygen species in WI-38 human lung cells.

Paraquat (methyl viologen, PQ) is a widely used herbicide that produces oxygen-derived free radicals and severely injures human lungs. In this study we examined the effects of PQ on the protein kinase C (PKC), ornithine decarboxylase (ODC) and c-jun oncogene expression in WI-38 human lung cells. Exposure of cells to 25-200 microM PQ resulted in an increase of [3H]phorbol dibutyrate (PDBu) binding and PKC redistribution in a dose-dependent manner. Interestingly, a superoxide dismutase mimic, 4-hydroxyl-2,2,6,6-tetramethyl-piperidine-1-oxyl (Tempol, 2.5 mM) and catalase (400 micrograms/ml) could significantly reduce the PQ-stimulated increase of phorbol ester binding and particular PKC phosphorylating activity, but dimethylsulfoxide (DMSO, 1.5%), an effective .OH trapping agent, failed to prevent this stimulation. In addition, an endogenous substrate of PKC, 80 kDa protein, was found to be highly phosphorylated in intact WI-38 cells treated with 50 microM PQ. The increase of phosphorylated proteins could be completely or partly abolished by Tempol or catalase, but only the phosphorylation of 80 kDa protein was diminished by protein kinase C inhibitor, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7). A maximal peak of ODC activity was observed at 6 h of treatment with 50 microM PQ. PQ induced activity was reduced at the following rates, Tempol 85%, DMSO 80% and catalase 45%, but H-7 failed to do so. Furthermore, we found that the level of c-jun mRNA was transiently increased by PQ and the peak appeared at 1 h of treatment. When correlated with the PKC result, Tempol, catalase and H-7 all effectively blocked PQ-elicited c-jun transcript expression, but DMSO only exhibited a weakly inhibitory effect. We therefore propose that superoxide anion (O2- and H2O2 generated by PQ could activate PKC and lead to induction of c-jun gene expression; on the other hand, O2- and .OH might trigger other kinase pathways to elevate ODC activity. Finally, the sequential expression of c-jun oncogene and ODC may cooperate to relieve the oxidative damages elicited by PQ.

Cell Line↗