[c-fos gene, c-jun gene].
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Amino Acid Sequence↗
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Differential c-jun gene expression with tonically administered steroids in rat ovary and uterus.
OBJECTIVE: The purpose of this study was to evaluate the induction of the early regulatory gene c-jun in response to tonic exposure to estradiol and progesterone in rat ovary, uterus, and adrenal tissues. STUDY DESIGN: Pellets containing estradiol-17 beta, progesterone, and estradiol-17 beta plus progesterone were placed subcutaneously in immature female Sprague-Dawley rats (N = 24). The ovary, uterus, and the adrenal were evaluated for c-jun expression by Northern analysis at 24 and 48 hours. RESULTS: The c-jun messenger ribonucleic acid expression in the ovary and adrenal gland was inhibited with high, nonphysiologic doses of estradiol in progesterone and was induced with physiologic levels of estradiol. Physiologic levels of progesterone do not appear to influence the expression of c-jun in the ovary or adrenal gland. Uterine c-jun expression to estradiol and progesterone is generally the opposite of that observed in the ovary. CONCLUSION: These findings suggest that there is both tissue and dose specificity of c-jun gene expression in steroidogenic and steroid-responsive tissues when steroid hormones are tonically administered.
Adrenal Glands↗
Activation of the tumor metastasis suppressor gene, KAI1, by etoposide is mediated by p53 and c-Jun genes.
KAI1 is a metastasis suppressor gene which is capable of inhibiting the processes of tumor metastasis without affecting tumorigenicity per se. We found that etoposide, a topoisomerase II inhibitor, is able to activate the expression of the KAI1 gene in a dose-dependent manner in human prostate cancer cell lines, ALVA, DU145, and PC-3 as well as in human lung carcinoma cell A549. The activation of the KAI1 gene was mainly mediated by the c-Jun gene in the PC-3 and DU145 cell lines, while it was mediated by both p53 and c-Jun genes in the A549 cell line. These results suggest that the augmentation of the KAI1 gene expression is independently controlled by p53 and c-Jun at the transcriptional level in the human cancer cell lines. Furthermore, treatment of these cell lines with etoposide resulted in significant reduction of cellular invasion measured by the Matrigel invasion chamber. Because etoposide has been shown to be effective on advanced prostate cancer when used in combination with other regimens, our results provide further rationale to use this drug as an antimetastatic agent.
5' Untranslated Regions↗
Inhibition of histone deacetylation by trichostatin A intensifies the transcriptions of neuronal c-fos and c-jun genes after kainate stimulation.
Kainate stimulation induces the expression of immediate early genes, c-fos and c-jun genes. Trichostatin A (TSA), a potent histone deacetylase (HDAC) enzyme inhibitor was used to test the role of histone hyperacetylation in the transcriptional regulation of c-fos and c-jun genes in neuronal cells in vivo and in vitro. Intraperitoneal administration of TSA increased histone H4 acetylation in hippocampi. Mice pretreatment with TSA were injected with kainic acid intraperitoneally and sacrificed over a time course of 12 h. Northern blot analysis and in situ hybridization showed that TSA pretreatment caused an increase in pre-existing basal levels of c-jun at 0 h and also intensified the maximal expression of both genes especially in the pyramidal layers of the hippocampus, thus demonstrating the inhibition of HDACs subsequently led to histone hyperacetylation to increase these genes expressions. TSA did not prolong the expression of c-fos or c-jun gene, in contrary to what we expected. Primary hippocampal neuron cell culture also displayed a similar pattern of c-fos and c-jun mRNA enhancement with trichostatin A pretreatment. This study demonstrated that inhibition of histone deacetylation by TSA in neuronal cells affect the expressions of c-fos and c-jun genes, suggesting histone acetylation might play a role in the regulation of both genes expressions after kainate stimulation.
Acetylation↗
p300 and ATF-2 are components of the DRF complex, which regulates retinoic acid- and E1A-mediated transcription of the c-jun gene in F9 cells.
Transcriptional activation of the c-jun gene is a critical event in the differentiation of F9 cells. In our previous studies we characterized an element [differentiation response element (DRE)] in the c-jun promoter that is both necessary and sufficient to confer the capacity for differentiation-dependent up-regulation. This element binds the differentiation regulatory factor (DRF) complex, of which one component is the adenovirus E1A-associated protein p300. We have now identified activation transcription factor-2 (ATF-2) as a DNA-binding subunit of the DRF complex. p300 and ATF-2 interact with each other in vivo and in vitro. The bromodomain and the C/H2 domain of p300 mediate the binding to ATF-2, which in turn requires a proline-rich region between amino acids 112 and 350 for its interaction with p300. The phosphorylation of the serine residue at position 121 of ATF-2 appears to be induced by protein kinase C alpha (PKC alpha) after treatment of cells with retinoic acid (RA) or induction with E1A. In cotransfection assays, wild-type ATF-2 enhanced the transcription of an E2/tk-luciferase construct, in conjunction with p300-E2. However, a mutant form of ATF-2 with a mutation at position 121 (pCMVATF-2(Ser121-Ala)) did not. These results suggest that ATF-2 and p300 cooperate in the control of transcription by forming a protein complex that is responsive to differentiation-inducing signals, such as RA or E1A, and moreover, that the phosphorylation of ATF-2 by PKC alpha is probably a signaling event in the pathway that leads to the transactivation of the c-jun gene in F9 cells.
Activating Transcription Factor 2↗
Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation.
Transforming growth factor beta (TGF beta) is a multifunctional polypeptide that regulates proliferation, differentiation, and other functions of many cell types. The pathway of TGF beta signal transduction in cells is unknown. We report here that an early effect of TGF beta is an enhancement of the expression of two genes encoding serum- and phorbol ester tumor promoter-regulated transcription factors: the junB gene and the c-jun proto-oncogene, respectively. This stimulation was observed in human lung adenocarcinoma A549 cells which were growth inhibited by TGF beta, AKR-2B mouse embryo fibroblasts which were growth stimulated by TGF beta, and K562 human erythroleukemia cells, which were not appreciably affected in their growth by TGF beta. The increase in jun mRNA occurred with picomolar TGF beta concentrations within 1 h of TGF beta stimulation, reached a peak between 1 and 5 h in different cells, and declined gradually to base-line levels. This mRNA response was followed by a large increase in the biosynthesis of the c-jun protein (AP-1), as shown by metabolic labeling and immunoprecipitation analysis. However, differential and cell type-specific regulation appeared to determine the timing and magnitude of the response of each jun gene in a given cell. In AKR-2B and NIH 3T3 cells, only junB was induced by TGF beta, evidently in a protein synthesis-independent fashion. The junB response to TGF beta was maintained in c-Ha-ras and neu oncogene-transformed cells. Thus, one of the earliest genomic responses to TGF beta may involve nuclear signal transduction and amplification by the junB and c-jun transcription factors in concert with c-fos, which is also induced. The differential activation of the jun genes may explain some of the pleiotropic effects of TGF beta.
Animals↗
Transcriptional regulation of the c-jun gene by AP-1 repressor protein JDP2 during the differentiation of F9 cells.
ATF-2 and p300 cooperate in the activation of transcription of the c-jun gene during the differentiation of F9 cells. We show here that a repressor of AP-1, JDP2 (Jun dimerization protein 2), inhibits the transactivation of the c-jun gene by ATF-2 and p300, by recruitment of a histone deacetylase complex, thereby repressing the retinoic acid (RA)-induced transcription of the c-jun gene and inhibiting the RA-mediated differentiation of F9 cells. Furthermore, JDP2/HDAC complex was replaced by p300 complex on the DRE (differentiation response element) of the c-jun promoter within 24 h after the start of exposure of cells to RA, with an accompanying change in the histone-acetylation status of the chromatin, indicating that the initiation of transcription of the c-jun gene was controled by sequential action of HDAC(s) and HAT(s) on c-jun promoter.
Animals↗
Selective down-regulation of c-jun gene expression by pentoxifylline and c-jun antisense interrupts platelet-derived growth factor signaling: pentoxifylline inhibits phosphorylation of c-Jun on serine 73.
Platelet-derived growth factor (PDGF) signals through several pathways, including mitogen-activated protein (MAP) kinase, Jun kinase, and C kinase, and stimulates proliferation of fibroblasts. Pentoxifylline inhibits PDGF-driven proliferation of fibroblasts. We have reported that pentoxifylline did not inhibit binding of PDGF to its specific cell-surface receptors or PDGF receptor phosphorylation. In this study, we investigated the effect of PDGF on the expression of c-fos and c-jun, because c-fos and c-jun form activator protein-1 complexes that stimulate genes involved in proliferation. We determined whether pentoxifylline would alter the expression of c-fos and c-jun. Our results indicate that PDGF induced the expression of both c-fos and c-jun. Pentoxifylline effectively reduced c-jun gene expression, which had been up-regulated by PDGF, but did not alter c-fos gene expression. The lack of effect on c-fos supports other studies from this laboratory, which indicate that pentoxifylline did not inhibit PDGF activation of MAP kinase. Treatment of fibroblasts with a phosphothioate c-jun antisense oligodeoxynucleotide reduced the levels of c-Jun protein and blocked PDGF-stimulated proliferation, suggesting a critical role for c-jun in PDGF-mediated proliferation. Combination of pentoxifylline and c-jun antisense suggested that they were likely inhibiting PDGF-stimulated proliferation at a single site in the PDGF signaling pathway. These results suggest that pentoxifylline inhibits PDGF-stimulated proliferation by selectively decreasing c-jun expression. To further define the mechanism of action of pentoxifylline, we assessed the effect of pentoxifylline on c-Jun and phosphorylated c-Jun immunoreactivity in cells treated with PDGF and cells that were transfected with wild-type c-jun plasmid using immunocytochemistry and Western blot analyses, and our results indicate that pentoxifylline inhibited phosphorylation of c-Jun on serine 73.
Animals↗
Regulation of c-jun gene expression in human T lymphocytes.
The present studies have examined the effects of mitogens on induction of early response gene expression in normal peripheral blood T and Jurkat cells. Pokeweed mitogen (PWM) or anti-CD3 significantly increases c-jun messenger RNA (mRNA) levels in T cells. This transient PWM-related increase in c-jun transcripts is maximal after 15 to 30 minutes of exposure of T cells to PWM. PWM induces c-jun gene expression in a concentration-dependent manner. Moreover, PWM similarly induces expression of other genes coding for leucine zipper transcription factors, ie, jun-B and c-fos. Nuclear run on assays demonstrate that PWM treatment is associated with an increased rate of c-jun gene transcription. Transient expression assays with c-jun promoter fragments linked to the chloramphenicol acetyltransferase gene suggest that the PWM-induced increase in transcription is mediated by the AP-1 transcription factor complex. Moreover, treatment of T cells with actinomycin D to block further transcription before their culture with PWM suggests that the increase in c-jun gene expression by PWM is also regulated at least in part by a posttranscriptional mechanism. Cycloheximide does not alter c-jun mRNA induction by PWM. Finally, given that PWM induces B-cell differentiation in an interleukin-6 (IL-6)-mediated, T-cell-dependent manner, the relationship of c-jun and IL-6 gene expression in PWM-stimulated T cells was examined. The induction of IL-6 mRNA in T cells stimulated by PWM occurs after maximal induction of c-jun mRNA, at a time when the latter is no longer detectable. These findings suggest that PWM induces c-jun gene expression in T cells by a transcriptional and posttranscriptional mechanism and that AP-1 confers PWM inducibility of this gene. Because the IL-6 promoter has several potential transcriptional control elements, one of which is an AP-1-binding site, future experiments will evaluate the role of c-jun in the regulation of PWM-induced IL-6 synthesis by T cells.
CD3 Complex↗
Coordinated induction of the c-jun gene with genes encoding quinone oxidoreductases in response to xenobiotics and antioxidants.
Xenobiotics and antioxidants induce expression of detoxifying enzymes including NAD(P)H: quinone oxidoreductase (NQO1), NRH:quinone oxidoreductase (NQO2), and glutathione S-transferase Ya (GST Ya), presumably to provide protection to cells against electrophilic and oxidative stress. Antioxidant response elements (AREs) have been found in the promoter regions of the various detoxifying enzyme genes. An ARE is required for basal expression and induction of the various detoxifying enzyme genes in response to xenobiotics and antioxidants. In this study, we demonstrated that exposure of cells to xenobiotics [e.g. beta-naphthoflavone (beta-NF)] and antioxidants [e.g. tert-butyl hydroquinone (t-BHQ)] also induced the expression of the proto-oncogene c-jun. The induction of c-jun gene expression followed kinetics similar to the induction of NQO1 and NQO2 genes with respect to the level and time of exposure. Sequence analysis of the c-jun gene promoter revealed the presence of an ARE between nucleotides -538 and -514. The c-jun ARE was highly homologous to the AREs from genes encoding NQO1, NQO2, and GST Ya. Constructs containing the c-jun ARE and 1.7 and 4.5 kb of the c-jun promoter ligated to the chloramphenicol acetyltransferase (CAT) gene, upon transfection in human hepatoblastoma (Hep-G2) cells, expressed the CAT gene, which was inducible with beta-NF and t-BHQ. Band shift assays indicated binding of two specific nuclear protein complexes with the c-jun gene ARE. The faster running c-jun gene ARE-nuclear protein complex was specifically competed out by unlabeled NQO1 and GST Ya gene AREs. These results suggest that c-jun gene expression is coordinately induced and regulated with detoxifying enzyme genes in response to xenobiotics and antioxidants. The results also suggest involvement of an ARE-mediated mechanism of induction of c-jun gene expression. However, a comparison of fold induction of endogenous c-jun gene and transfected c-jun promoter/ARE-CAT constructs indicated involvement of another ARE upstream of the 4.5-kb promoter and/or additional mechanisms such as stabilization of c-Jun RNA in response to exposure to xenobiotics and antioxidants.
Antioxidants↗
Identification of NF-jun, a novel inducible transcription factor that regulates c-jun gene transcription.
In this study we report the identification of a novel transcription factor, termed Nuclear Factor-jun (NF-jun). This factor contributes to inducible transcription of the c-jun gene in human myeloid leukemia cells. NF-jun was, however, undetectable in nuclear proteins from human monocytes, granulocytes, resting T lymphocytes and lung fibroblasts. NF-jun shares several features with the well characterized NF-kappa B in that binding activity can be generated in cytosolic extracts by treatment with dissociating agents. In addition, binding of NF-jun to its recognition site is enhanced by treatment of cells with 12-O-tetradecanoylphorbol-13-acetate, tumor necrosis factor alpha or the protein synthesis inhibitor cycloheximide (CHX). However, as revealed by competition assays and electrophoretic mobility shift assays, purified NF-kappa B fails to bind to the c-jun fragment which contains the NF-jun site, and this fragment fails to compete with NF-kappa B for binding. UV crosslinking showed that NF-jun contains a 55 and a 125 kDa protein species. These findings demonstrate that the c-jun gene can be regulated by a transcription factor distinct from AP-1. Our findings also indicate that while NF-jun has several features in common with the NF-kappa B binding protein including its subcellular localization and its ability to translocate from the cytoplasm to the nucleus, this factor recognizes a unique DNA sequence. Moreover, the activity of this protein is differentially regulated in various cell types. NF-jun might function as a signal transducing molecule in order to mediate rapid induction of the early response gene c-jun in a cell type- and stimulus-specific manner.
Base Sequence↗
Expression of the transin, c-fos, and c-jun genes in rat transplantable osteosarcomas and malignant fibrous histiocytomas.
The expression of the transin, c-fos, and c-jun genes was assessed in transplantable osteosarcomas and malignant fibrous histiocytomas, as well as in pancreatic duct adenocarcinomas and hepatocellular carcinomas of rats and hamsters. Northern blot analysis revealed that both an undifferentiated osteosarcoma of spontaneous origin (SOS) and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced malignant fibrous histiocytomas with metastatic potential to the lung showed remarkably increased expression of transin mRNA transcripts. This was not the case for the other tumors. Interestingly, levels of transin mRNA were lower in lung metastatic lesions than in primary subcutaneous SOS tumors. The primary SOS and MFH expressed both c-fos and c-jun genes in conjunction with the transin gene, whereas the non-transin expressers, a 4-HAQO-induced osteosarcoma (COS) and the pancreatic duct adenocarcinomas, demonstrated one or the other, but not both. These results suggest a possible involvement of transin expression in the progression of spontaneous osteosarcomas and 4-HAQO-induced malignant fibrous histiocytomas in rats. Expression of the c-fos and c-jun genes may play a regulatory role in this process.
4-Hydroxyaminoquinoline-1-oxide↗
Heterogeneity in c-jun gene expression in normal and malignant cells exposed to either ionizing radiation or hydrogen peroxide.
We investigated the role of reactive oxygen intermediates and protein kinase C in the induction of expression of the c-jun gene in human ML-2 leukemic cells and normal human DET-551 fibroblasts by comparing the effects of exposure to either ionizing radiation or H2O2 in the presence or absence of appropriate inhibitors. In these cell types, the radiation- and H2O2-mediated increase in c-jun mRNA levels could be prevented by pretreatment of the cells with N-acetylcysteine, an antioxidant, or H7, an inhibitor of protein kinase C and protein kinase A, but not by HA1004, a specific inhibitor of protein kinase A and G. These results suggest a role for protein kinase C and reactive oxygen intermediates in the induction of c-jun gene expression in both normal and tumor cells. We also investigated potential differences in c-jun gene expression induced by radiation or H2O2 in normal and tumor cells by examining steady-state c-jun mRNA levels in a number of human fibroblast, leukemia, melanoma, sarcoma and carcinoma cell types. We observed heterogeneity in the steady-state level of c-jun mRNA in both the untreated normal and tumor cells and in such cells exposed to ionizing radiation or to H2O2. Exposure to radiation produced a varied response which ranged from little or no induction to an increase in the steady-state level of the c-jun mRNA of more than two orders of magnitude. Exposure to H2O2 gave a pattern similar to that of ionizing radiation. The basis for the differential induction in response to these agents may be attributable to either cell lineage or genetic heterogeneity or a combination of these two parameters.
Base Sequence↗
Expression of fos and jun genes in human skeletal muscle after exercise.
It is believed that the induction of the fos and jun gene family of transcription factors might be at the origin of genetic events leading to the differential regulation of muscle-specific genes. We have investigated the effect of a 30-min running bout in untrained subjects on the expression of the mRNAs of all members of the fos and jun gene families, including c-fos, fosB, fosBdel, fra-1, and fra-2 as well as c-jun, junB, and junD. While the fos family members were transiently upregulated 10- to 20-fold (an exception being fra-2) the induction of the jun family members was up to 3-fold only. The induction of c-fos could also be demonstrated at the protein level. Both c-fos and c-jun mRNAs were coinduced in muscle fiber nuclei. The induction was not restricted to a particular fiber type, as expected from established muscle fiber recruitment schemes, but followed a "patchy" pattern confined to certain regions of the muscle. The signals leading to the expression of these immediate early genes are therefore unclear.
Adult↗
Stimulation of muscarinic receptors induces expression of individual fos and jun genes through different transduction pathways.
The transduction pathways coupling muscarinic receptors to induction of fos and jun genes were investigated in neuroblastoma SH-SY5Y cells. Stimulation with carbachol induced expression of c-fos, fosB, c-jun, junB, and junD. This effect was abolished by pretreatment with atropine, indicating an involvement of muscarinic receptors. These genes were also induced by activation of protein kinase C with phorbol ester or by elevating the intracellular Ca2+ concentration with a Ca2+ ionophore. The Ca2+ effect was inhibited by KN-62, suggesting an induction through Ca2+/calmodulin-dependent kinase II. Inhibition of protein kinase C with GF109203X suppressed the carbachol-stimulated increase in mRNA levels of c-fos, fosB, and junB by approximately 70% but had only minor effects on the expression of c-jun and junD. On the other hand, preincubation with KN-62 attenuated the carbachol-induced increase in c-jun and junD expression by 70% but had no effect on c-fos, fosB, and junB mRNA levels. Simultaneous inhibition of both protein kinase C and Ca2+/calmodulin-dependent kinase II completely abolished the carbachol-stimulated expression of c-jun and junD, but c-fos, fosB, and junB were still expressed to a certain extent under this condition. Comparison of the inhibitory effects of GF109203X and Gö 6976 suggests the involvement of classical protein kinase C isozymes in muscarinic receptor-stimulated expression of fos and jun genes. These results demonstrate that the muscarinic receptor-induced expression of individual fos and jun genes is regulated via different pathways, primarily protein kinase C or Ca2+/calmodulin-dependent kinase II.
Calcium↗
Ginsenosides inhibit EGF-induced proliferation of renal proximal tubule cells via decrease of c-fos and c-jun gene expression in vitro.
Recent epidemiological studies have demonstrated that ginseng intake is associated with a reduced risk for environmentally related cancers. However, the effects of ginsenosides on the proliferation of renal proximal tubule cells have not yet elucidated. This study investigated the effect of total ginsenosides, protopanaxatriol (PT) saponin, and protopanaxadiol (PD) saponin fraction on epidermal growth factor (EGF)-induced renal cell proliferation and, furthermore, c-fos and c-jun gene expression. In the present study, total ginsenosides (10 -6 g/ml) completely blocked EGF-induced DNA synthesis and cell growth. In contrast, the PT and PD fractions partially blocked it. In addition, the EGF-induced increase of c-fos and c-jun gene expression was completely blocked by total ginsenosides and partially by PT and PD saponins. In conclusion, ginsenosides, in part, inhibit EGF-induced cell proliferation via decrease of c-fos and c-jun gene expression in primary cultured rabbit renal proximal tubular cells (PTCs). Abbreviations. EGF:epidermal growth factor PD:protopanaxadiol PT:protopanaxatriol PTCs:primary cultured renal proximal tubule cells
Animals↗
[Effects of fluoride on the expression of c-fos and c-jun genes and cell proliferation of rat osteoblasts].
OBJECTIVE: To investigate the effects of sodium fluoride (NaF) on the expression of c-Fos and c-Jun genes and osteoblast cell proliferation of rat osteoblasts. METHODS: Osteoblastic cells were isolated from baby rat calvaria, and cultured in the presence of different doses of NaF (10(-5) mol/L, 10(-4) mol/L, and 10(-3) mol/L). Cell proliferation was measured by the MTT method, and c-Fos and c-Jun expression was detected by the immunohistochemistry combined with image analysis compute system. RESULTS RESULTS: from the MTT assay showed that NaF increased the proliferation of rat osteoblast and induced the expression of c-Fos and c-Jun genes. The increases of c-Fos and c-Jun expression by the 3 different doses of NaF were 5.4%, 15.4% and 42.3% for the c-Fos gene and 12.1%, 14.4% and 38.6% for c-Jun gene respectively (P < 0.05 and P < 0.01). CONCLUSION: NaF increased rat osteoblastic cell proliferation and the expression of genes involved in cell proliferation.
Animals↗
Clonidine diminishes c-jun gene expression in the cardiovascular sensitive areas of the rat brainstem.
The present study investigated the effect of clonidine on the basal and inducible c-jun and c-fos mRNA expression in the nucleus tractus solitarius (middle, mNTS, and rostral, rNTS) and the rostral ventrolateral medulla (caudal, cRVLM, and rostral, rRVLM). Conscious rats received saline, clonidine (30 microg/kg, i.v.), saline plus sodium nitroprusside (NP), or clonidine plus NP. Under basal conditions (saline-infused rats), c-jun mRNA was expressed in the mNTS and rRVLM but not in the rNTS or cRVLM whereas c-fos mRNA was not detectable. Clonidine attenuated the increases in c-fos in the mNTS and cRVLM and c-jun gene expression in the mNTS and rRVLM caused by NP-evoked hypotension and also reduced the basal expression of c-jun mRNA in the mNTS and rRVLM. These findings establish a causal link between clonidine inhibition of c-fos expression in brainstem and its hypotensive action, and provide the first evidence that clonidine attenuates the expression of the closely linked c-jun gene in neurons implicated in centrally mediated hypotension.
Animals↗