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PubMed1993

B cell development is perturbed in bone marrow from c-fos/v-jun doubly transgenic mice.

c-fos and c-jun gene products form a heterodimeric complex (AP-1) that regulates target gene expression by binding to a specific DNA sequence motif. In order to study a role of AP-1 (Fos/Jun) in growth and differentiation of immature B lineage cells, we have established and mated two independent transgenic mice carrying the mouse c-fos gene or the viral v-jun gene fused to the H-2K promoter. IL-7 dependent bone marrow cell culture from doubly transgenic (H2-fos/jun) mice demonstrated severe delay of early B cell development. Proliferation of pre-B cells in the fresh bone marrow from H2-fos/jun mice to IL-7 stimulation was very low. These results suggest that the deregulated production of AP-1 perturbs IL-7 mediated proliferation and differentiation of immature B cells.

Animals↗

PubMed2002

JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells.

Up-regulation of the c-jun gene is a critical event in the retinoic acid (RA)-mediated differentiation of embryonal carcinoma F9 cells. Activating transcription factor 2 (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 the overexpression of Jun dimerization protein 2 (JDP2), a repressor of AP-1, inhibits the transactivation of the c-jun gene by ATF-2 and p300 by recruitment of the histone deacetylase 3 (HDAC3) complex, thereby repressing the RA-induced transcription of the c-jun gene and inhibiting the RA-mediated differentiation of F9 cells. Moreover, chromatin immunoprecipitation assays showed that the JDP2/HDAC3 complex, which binds to the differentiation response element within the c-jun promoter in undifferentiated F9 cells, was replaced by the p300 complex in response to RA, with an accompanying change in the histone acetylation status of the chromatin, the initiation of transcription of the c-jun gene, and the subsequent differentiation of F9 cells. These results suggest that JDP2 may be a key factor that controls the commitment of F9 cells to differentiation and shed new light on the mechanism by which an AP-1 repressor functions.

Activating Transcription Factor 2↗

PubMed1994

Transforming growth factor-beta relieves stem cell factor-induced proliferation of myelogenous leukemia cells through inhibition of binding of the transcription factor NF-jun.

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of growth factor-stimulated hematopoiesis in normal and leukemic conditions. Using the factor-dependent myelogenous leukemia cell lines GF-D8 and Mo7, we show that TGF-beta interferes with stem cell factor (SCF)-induced proliferation by downmodulating c-jun gene expression. The ability of SCF to induce accumulation of c-jun transcripts was abolished when TGF-beta was present in culture. Transcriptional nuclear run-on assays indicated that TGF-beta relieved the capacity of SCF to enhance the transcriptional rate of the c-jun gene. Deletion analysis of the c-jun promoter furthermore showed that SCF was activating the c-jun promoter via the NF-jun transcription factor. Gel mobility shift assays showed that SCF increased the binding activity of NF-jun to its recognition site within 5 to 15 minutes. Binding activity peaked at 1 hour after exposure to SCF and declined to starting levels within 4 hours. The ability of SCF to enhance NF-jun binding activity was also dose-dependent in the range of 5 to 100 ng/mL. Exposure of GF-D8 and Mo7 cells to TGF-beta before the addition of SCF antagonized SCF-induced NF-jun binding. Moreover, whereas SCF was capable of functionally activating a heterologous promoter containing the NF-jun binding site, pretreatment of GF-D8 cells with TGF-beta abolished transcriptional activation of this heterologous promoter. These findings indicate that SCF-mediated activation of c-jun via NF-jun is crucial for the SCF-inducible proliferative response and is inhibited by TGF-beta. In additional experiments, the antisense technique was used. Treatment of GF-D8 and Mo7 cells with an antisense oligodeoxyribonucleotide directed against the translation initiation site of c-jun abolished the capacity of SCF to induce a proliferative response, whereas sense and nonsense oligomers had no effect. Taken together, our data indicate that the counteracting modulation of the binding activity of NF-jun by SCF and TGF-beta regulates the expression of the c-jun gene and thereby the proliferative state of the GF-D8 and Mo7 target.

Binding Sites↗

PubMed1991

Expression of the jun-B gene during induction of monocytic differentiation.

The AP-1 protein complex binds to specific DNA sequences that regulate transcription of genes responsive to certain growth factors and phorbol esters. This complex is composed of products of the jun and fos gene families. The present studies have examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the regulation of jun-B gene expression during induction of monocytic differentiation. Low levels of jun-B transcripts were present in uninduced HL-60 promyelocytic leukemia cells. In contrast, treatment with TPA was associated with rapid increases in jun-B mRNA levels that were maximal at 3 h and remained elevated at 48 h. The induction of jun-B expression by TPA in these cells preceded that of the c-jun and c-fos genes. Similar increases in jun-B transcripts were detectable in TPA-treated THP-1 and U-937 myeloid leukemia cells, although expression of this gene was transient in the more differentiated THP-1 cells. Run-on assays demonstrated low levels of jun-B gene activation in untreated HL-60 cells, whereas TPA treatment was associated with a 6-fold increase in the transcription rate of this gene. This induction of jun-B expression occurred in the absence of de novo protein synthesis. In contrast, inhibition of protein synthesis was associated with superinduction of TPA-induced jun-B mRNA levels and an increase in stability of this transcript. These findings suggest that jun-B gene expression is regulated at both the transcriptional and posttranscriptional levels during induction of monocytic differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bryostatins↗

PubMed1999

Functional analysis of the transcriptional coactivators p300 and CBP using ribozyme.

p300 and CERB binding protein (CBP) are transcriptional coactivator which participate many signal transduction pathways via interaction with DNA binding proteins. In this study, we investigated functions of p300 and CBP during the retinoic acid (RA) induced F9 cell differentiation using hammerhead ribozymes. In wild type F9 cells, induction of c-jun gene was observed at 18 h after treatment with RA. Interestingly, RA-dependent expression of c-jun gene was not induced in cells expressing the p300-directed ribozyme. By contrast, the CBP-directed ribozyme did not affect expression of the c-jun gene. These results suggest that p300 is critical for the induction of c-jun gene during RA-induced differentiation.

Animals↗

PubMed1992

Selective effects of pentobarbital and halothane on c-fos and jun-B gene expression in rat brain.

The effects of pentobarbital and halothane anesthesia on the expression in brain of the immediate-early genes c-fos and jun-B were investigated. Pentobarbital-anesthetized rats (n = 10) received a single intraperitoneal injection of pentobarbital 65 mg/kg in a vehicle of 40% propylene glycol and 10% ethanol and then were placed in a plexiglass box flushed continously with 100% oxygen at 5 l/min. Halothane-anesthetized rats (n = 10) received an intraperitoneal injection of vehicle only and were transferred to a box flushed continuously with oxygen plus 1.5% halothane. Unanesthetized control rats (n = 10) received an intraperitoneal injection of vehicle and were placed in a box flushed continuously with 100% oxygen. Four additional rats received no intraperitoneal injection but were handled and otherwise treated identically to the control group, and six others had a femoral arterial catheter inserted for blood pressure and blood gas measurements. Five animals from the control and both anesthetized groups were killed at 30 and 120 min postinjection and their brains rapidly removed and frozen. The messenger ribonucleic acid transcription products of the genes c-fos, jun-B, and beta-actin from whole cerebral hemispheres were analyzed autoradiographically after Northern blot hybridization with 32P-labeled deoxyribonucleic acid probes. Relative levels of c-fos and jun-B messenger ribonucleic acid were determined from optical density measurements of the autoradiographic bands, with beta-actin measurements being used to correct for sample-to-sample variation. Rats became immobile within minutes of drug administration and remained anesthetized until they were killed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

CRF stimulates expression of multiple fos and jun related genes in the AtT-20 corticotroph cell.

Recent studies have shown that corticotropin releasing factor (CRF) stimulates c-fos gene expression in the AtT-20 corticotroph cell line, and that overexpression of c-Fos results in activation of POMC gene transcription. Since transactivation by c-Fos requires dimerization with a Jun family member to form the active transcription factor AP-1, we have examined the expression of multiple fos and jun related genes and have correlated their expression with AP-1 DNA binding activity in AtT-20 nuclear extracts after stimulation with CRF. Although basal expression of c-fos mRNA was extremely low, it was rapidly and transiently stimulated in AtT-20 cells following administration of either constant or a single pulse of CRF. In contrast, basal expression of c-jun mRNA was slightly higher and underwent little or no change in response to CRF. Specific ribonuclease protection analysis showed that in addition to c-fos, mRNA transcripts encoding fos B and jun B were rapidly stimulated in response to CRF, though levels of induced fos B mRNA were 20-40 times lower than c-fos or jun B, respectively. Gel shift analysis demonstrated that CRF caused a sustained increase in AP-1 DNA binding to both a canonical AP-1 element as well as to the POMC exon-1 AP-1 site. Studies with specific antisera directed against c-Fos revealed that although no c-Fos could be detected in AP-1 complexes in basal cell extracts, c-Fos became a prominent component of AP-1 following CRF stimulation, reaching maximal levels by 4 h. Despite the fact that AP-1 DNA binding activity remained elevated for at least 24 h after CRF, c-Fos was most prominent during the early phase of the response. Similarly, JunB was shown to be a major component of AP-1 DNA binding activity in CRF-stimulated AtT-20 nuclear extracts that persisted for at least 24h after stimulation. Despite the obvious induction of fos B mRNA in response to CRF, FosB protein was not detected in DNA bound AP-1 complexes. These data demonstrate that CRF is a potent stimulus for corticotroph expression of c-fos, jun B and fos B, and suggest that the subsequent increase in AP-1 may play a role in activation of gene expression and/or as a modulator of glucocorticoid receptor function.

Animals↗

PubMed1994

Follicle-stimulating hormone regulation of AP-1: inhibition of c-jun and stimulation of jun-B gene transcription in the rat Sertoli cell.

The proto-oncogenes c-fos and c-jun and the related jun-B encode the components of transcription factor, AP-1, a heterodimeric DNA-binding protein that mediates hormone and growth factor-regulated gene expression. In the rat Sertoli cell, FSH rapidly inhibited c-jun gene expression while it stimulated c-fos and jun-B as well as the expression of the more slowly responding, tissue plasminogen activator (tPA) and inhibin alpha-subunit. These early effects of FSH were not inhibited by cycloheximide. Nuclear run-off analyses demonstrated that the FSH-dependent decline in c-jun and increases in c-fos, jun-B, tPA and inhibin alpha-subunit mRNAs were regulated at the transcriptional level. The rates of degradation of c-fos, c-jun and jun-B mRNAs were unaffected by FSH while tPA and inhibin alpha-subunit mRNAs were stabilized. After 8 h of FSH treatment, the transcription of all five genes returned to basal rates. These data demonstrate immediate-early regulation by FSH of the expression of genes encoding components of the transcription factor, AP-1.

Animals↗

PubMed1995

Expression of jun family genes in rat retinal cells: regulation by light/dark cycle.

The expression of jun family genes in the retina of rats raised under a 12 h light/12 h dark cycle (LD 12:12) was examined by in situ hybridization histochemistry. c-jun and jun B mRNAs were found to be expressed in the inner nuclear layer (INL) which consists of horizontal, bipolar and amacrine cells and in the ganglion cell layer (GCL) which consists of ganglion cells and displaced amacrine cells and this expression was induced following the onset of the light. The expression of both mRNAs reached maximal levels by 30 min and then declined to low levels 2 h after light onset. In contrast, high levels of jun D mRNA were constitutively expressed and this expression was not confined to the INL and the GCL since it was also present in the ONL. Together with our previous report that c-fos was expressed transiently in the INL and the GCL after the onset of the light period and constitutively in the ONL throughout the dark period, the colocalization of c-fos with c-jun, jun B and jun D in the INL and the GCL after light onset and with jun D in the ONL during the dark period suggests that Jun and Fos proteins form an active AP-1 transcription factor which plays a key role in gene regulation in retinal cells.

Animals↗

PubMed1993

Correlation between lack of bone Gla protein mRNA expression in rat transplantable osteosarcomas and expression of both c-fos and c-jun proto-oncogenes.

Alkaline phosphatase (AP) activity and expression of bone Gla protein (BGP), c-fos, and c-jun were compared in two transplantable osteosarcomas with high potentials for metastasis to the lung. The original spontaneous osteosarcoma (SOS) gradually became histologically undifferentiated, losing its osteogenic activity during serial transfer, whereas the chemical (4-hydroxyaminoquinoline 1-oxide)-induced osteosarcoma (COS) retained osteogenesis. The two osteosarcomas showed similar doubling times and levels of lung metastasis, and strong AP activity was detected on the cell membranes of both. Northern blot analysis revealed that lack of BGP mRNA expression was associated with expression of both c-fos and c-jun proto-oncogenes in SOS. In contrast, neither c-fos nor c-jun mRNAs were detected but BGP mRNA was expressed in the case of COS. These results suggest that the c-fos and c-jun genes may suppress the expression of BGP mRNA relevant to differentiation and osteoid formation in rat osteosarcomas. However, this does not appear to be directly related to proliferative or metastatic biological behavior.

Alkaline Phosphatase↗

PubMed1995

Membrane immunoglobulin receptor cross-linking induces fosB mRNA expression in mature B lymphocytes: assembly of distinct FosB-containing nucleoprotein complexes during B cell stimulation.

We demonstrate herein that anti-Ig stimulation of Bal-17 B cells leads to a rapid and transient increase in fosB mRNA levels, with kinetics similar to those previously reported for members of the jun gene family. The coupling of fosB expression to known protein kinases that are activated following membrane immunoglobulin receptor (mIg) cross-linking was evaluated. Inhibition of src-protein tyrosine kinase activity by pretreatment of Bal-17 B cells with herbimycin A prevented subsequent anti-Ig-dependent increases in fosB mRNA levels. Moreover, inhibition of protein kinase C (PKC) by pretreatment of Bal-17 B cells with staurosporine, H7, or by phorbol ester-induced down-regulation of PKC activity blocked anti-Ig-stimulated fosB gene expression. These findings suggest that fosB expression is coupled to a mIg-mediated pathway that utilizes activated src-protein tyrosine kinases and PKC. Immunoblotting of Bal-17 B cell extracts with anti-FosB antiserum revealed that mIg cross-linking results in an increase in FosB protein levels. Moreover, immunoprecipitation of nondenatured Bal-17 B cell extracts indicated that FosB forms complexes in vivo with JunB and JunD and to a lesser extent with cJun. The anti-Ig-induced FosB/Jun complexes bind to several distinct cis-acting DNA elements, including AP-1 and NF-AB, which have been implicated in regulating nuclear gene expression during B cell activation. Collectively, these results suggest that FosB plays a central role in regulating gene expression during anti-Ig-mediated B cell activation.

Animals↗

PubMed1996

The regulation mechanism of c-jun and junB by human papillomavirus type 16 E5 oncoprotein.

In this study, we show that HPV-16 E5 induced anchorage-independent growth in immortalized human epidermal keratinocytes and that HPV-16 E5 in human keratinocytes had higher expression of c-jun and junB; also, we investigated the role of transcriptional initiation pathways in the expression elevation. In addition, Ras-dependent pathway, as well as PKC-dependent pathway, leads to HPV-16 E5-induced c-jun gene expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1998

Increased jun immunoreactivity in an in vitro model of mammalian spinal neuron physical injury.

Dendrites were transected from murine spinal neurons. Unlesioned neurons showed dark nucleolar and patchy cytoplasmic jun immunostaining. By 0.5 and 2 h, most lesioned neurons stained intensely throughout the soma. However, at 24 h only dead neurons displayed intense somal staining, and 100% of the surviving cells stained like unlesioned controls. Correlation of immunostaining patterns with viability, injury, and death suggests jun gene expression may influence the survival of neurons after physical injury.

Animals↗

PubMed2004

Fibroblast growth factor-2 stimulates interleukin-6 secretion in human pancreatic periacinar myofibroblasts.

OBJECTIVES: Fibroblast growth factor-2 (FGF-2) plays an important role in the pathophysiology of acute and chronic pancreatitis. In the present study, to evaluate the proinflammatory nature of FGF-2, we investigated the effects of FGF-2 on IL-6 secretion in human pancreatic periacinar myofibroblasts. METHODS: IL-6 supernatant levels were determined by enzyme-linked immunosorbent assays (ELISA). IL-6 mRNA expression were determined by Northern blots and quantitative PCRs. Activated protein (AP)-1 DNA-binding activities were evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: FGF-2 induced IL-6 release in a dose- and time-dependent manner. FGF-2 activity for IL-6 induction was the same as that of IL-17. The combination of FGF-2 and IL-17 exerted additive effects at mRNA and protein levels. FGF-2 induced AP-1 DNA-binding activity, but blockage of AP-1 signaling by adenovirus-mediated transfer of a dominant negative c-Jun gene did not affect FGF-2-induced IL-6 mRNA expression. FGF-2 rapidly induced activation of ERK1/2 and p38 MAP kinases, and specific inhibitors for these enzymes significantly reduced FGF-2-induced IL-6 release. CONCLUSION: In the pancreas, FGF-2 may not only play a role as a growth factor in tissue injury repair processes but also as an inducer of acute-phase response via stimulation of IL-6 release.

Adenoviridae↗

PubMed1992

Regulation of genetic expression in shear stress-stimulated endothelial cells.

There is increasing evidence that endothelial cells respond to the initiation of mechanical stress by the generation of certain second messengers and the activation of specific metabolic pathways. These rapid alterations in cellular function are accompanied by alterations in protein synthesis that are detectable several hours after initiation of the mechanical stress. The molecular mechanisms by which changes in the cytosol are converted to altered genetic expression in the nucleus are not known. Because agonist-induced modulations in the rate of synthesis of tPA and ET have been associated with the Fos and Jun protein families, it seems reasonable to propose that genetic expression in shear stress- or mechanical strain-stimulated endothelial cells is also regulated by selective induction of fos and jun gene products. Testing of this hypothesis is actively under way in our laboratory.

Amino Acid Sequence↗

PubMed1997

Differences in mRNA expression of endothelin-1, c-fos and c-jun in placentas from normal pregnancies and pregnancies complicated with preeclampsia and/or intrauterine growth retardation.

A defect in placental function has been suggested to be associated both with preeclampsia (PE), with or without concomitant intrauterine growth retardation (IUGR), and with IUGR as a single entity. Our aim was to compare the mRNA expression of the growth-related protooncogenes c-fos and c-jun and the vasoconstrictor and growth factor endothelin-1 (ET-1) in placentas from normal pregnancies with those of PE and IUGR. The mRNA expression of c-jun was significantly higher in all groups of complicated pregnancies while ET-1 and c-fos mRNA expression was significantly higher only in the group with IUGR. These results support the concept that an aberrant placental mRNA expression of the ET-1, c-fos and c-jun genes is part of an altered pattern of gene expression in pathological pregnancies.

Biopsy↗

PubMed1997

Activation of mitogen-activated protein kinases (ERK/JNK) and AP-1 transcription factor in rat carotid arteries after balloon injury.

Smooth muscle cell proliferation is a key event in neointimal formation after balloon angioplasty. The molecular signals that mediate this process have yet to be identified. Mitogen-activated protein (MAP) kinases are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate whether the signal transduction pathways of MAP kinases were involved in the development of restenosis in the injured arteries. Rat carotid arteries were isolated at various time points after balloon injury, and activities of MAP kinases, including extracellular signal-regulated kinases (ERK), and stress activated protein kinases (SAPK)/c-Jun N-terminal protein kinases (JNK), were determined in protein extracts of the vasculature using protein kinase assay and Western blot analysis. After balloon angioplasty, ERK2 and JNK1 activities in the vessel wall increased rapidly, reached a high level in 5 minutes and maintained for 1 hour. A sustained increase in ERK2 kinase activity was observed over the next 7 days in the arterial wall and 14 days in neointima after injury. In contrast, opposite and uninjured arteries did not show significant changes in these kinase activities. Concomitantly, Western blot analysis confirmed that the ERK2 kinase in the injured vessels was indeed activated or phosphorylated, showing a slowly migrating species of a 42-kDa protein containing phosphorylated tyrosine. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced activator protein 1 (AP-1) DNA-binding activity. Thus, balloon injury rapidly activates the MAP kinases in rat carotid arteries. These kinase activations may be crucial in mediating smooth muscle cell proliferation in response to vascular angioplasty.

Angioplasty, Balloon↗

PubMed1998

Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells.

Lysophosphatidylcholine (lyso-PC) has been implicated in atherogenesis and the inflammatory process. Although lyso-PC has been reported to contribute to the mitogenic effect of oxidized LDL on rat cultured vascular smooth muscle cells (VSMCs), the signaling mechanisms by which lyso-PC promotes its proliferation are poorly characterized. Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduces extracellular cues to intracellular responses. We therefore examined the effect of lyso-PC on MAP kinase activation, proto-oncogene expression, and AP-1 binding activity using cultured rat VSMC. Marked activation of MAP kinase occurred within 10 minutes of lyso-PC treatment, whereupon rapid inactivation ensued. MAP kinase activation by lyso-PC was concentration-dependent (6.25 to 25 micromol/L). Pertussis toxin treatment did not affect lyso-PC-induced MAP kinase phosphorylation. Lyso-PC (25 micromol/L) also increased the mRNA expression of c-fos and c-jun genes. An electrophoretic mobility shift assay showed that AP-1 binding activity was enhanced by lyso-PC. To examine the upstream signaling of MAP kinase, we used several inhibitors on MAP kinase activation induced by lyso-PC. Although lyso-PC induced sustained increase in intracellular Ca2+ concentration, EGTA had no effect on MAP kinase activation induced by lyso-PC. However, protein kinase C inhibitor GF109203X and downregulation of protein kinase C activity by prolonged treatment with phorbol ester inhibited lyso-PC-induced MAP kinase activation. These data suggest that lyso-PC transmits its mitogenic activity through a MAP kinase-AP-1 pathway, which exists downstream of its protein kinase C activation in VSMCs.

Animals↗