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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↗
PubMed2005

The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase.

The c-Jun and c-Myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-Myc, we report here that phosphorylation of c-Jun by GSK3 creates a high-affinity binding site for the E3 ligase Fbw7, which targets c-Jun for polyubiquitination and proteasomal degradation. In keeping with this, we found that c-Jun levels were inversely related to GSK3 activity in mammalian cells that had entered the cell cycle. Importantly, phosphorylation of c-Jun by GSK3 requires a priming phosphorylation event at Ser-243. Ser-243 is mutated to phenylalanine in v-Jun and allows it to escape recognition by Fbw7. These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc.

Binding Sites↗
PubMed1996

Stepwise transformation of rat embryo fibroblasts: c-Jun, JunB, or JunD can cooperate with Ras for focus formation, but a c-Jun-containing heterodimer is required for immortalization.

Among the Jun family of transcription factors, only c-Jun displays full transforming potential in cooperation with activated c-Ha-Ras in primary rat embryo fibroblasts. c-Jun in combination with Ras can both induce foci of transformed cells from rat embryo fibroblast monolayers and promote the establishment of these foci as tumoral cell lines. JunB can also cooperate with Ras to induce foci but is unable to promote immortalization. We report here that JunD, in cooperation with Ras, induces foci with an efficiency similar to that of JunB. Artificial Jun/eb1 derivatives from each of the three Jun proteins were also analyzed. These constructs carry a heterologous homodimerization domain from the viral EB1 transcription factor and are thought to form only homodimers in the cell. We show here that these Jun/eb1 chimeras are potent transactivators of AP1 sites and that they can cooperate with c-Ha-Ras to induce foci. However, among all the Ras-Jun and Ras-Jun/eb1 combinations tested, only foci from Ras-c-Jun can be efficiently expanded and maintained as long-term growing cultures. Therefore, we suggest that a heterodimer containing c-Jun might be required for in vitro establishment of these primary mammalian cells.

Animals↗
PubMed1991

C-jun and jun-B oncogene expression during placental development.

During embryogenesis, growth and differentiation occur in a sequential, predetermined order suggesting that specific genes are turned on and off in a precise and well-regulated manner. Placental development, which is characterized by massive proliferation and differentiation of multiple cell types, must be similarly regulated. Early response protooncogenes, such as c-jun and jun-B, have been associated with both proliferation and differentiation of different cell types. In this study, using Northern blot analysis, we found that c-jun and jun-B expression occurred in human placentas throughout gestation. Maximal expression of c-jun occurred in early gestation, and maximal expression of jun-B occurred in late gestation. We speculate that peak expression of c-jun in human placenta at early gestation may be related to cytotrophoblastic proliferation and that peak expression of jun-B in late gestation may be related to further terminal differentiation of trophoblastic cells.

Blotting, Northern↗
PubMed1995

Charting of Jun family member proteins in the rat forebrain and midbrain: immunocytochemical evidence for a new Jun-related antigen.

Immunocytochemistry was used to localize members of the Jun family of immediate-early genes in the forebrain and midbrain of non-stimulated male rats. Antibodies against specific peptide sequences of c-Jun (Ab-1 and Ab-2 from Oncogene Science) and against expressed proteins of JunB and JunD (both from Dr. R. Bravo) revealed widespread and unique distributions for each of these antigens. Charts were made of the distribution of each antigen, and extensive comparisons were made of previous results obtained using in situ hybridization to localize mRNAs for c-jun, junB and junD. Our results indicate a generally favorable comparison between immunoreactivity and distribution of mRNAs for JunB and JunD, but in the case of c-Jun, immunoreactivity and mRNA were comparable only with the Ab-1 antibody. Indeed, the immunocytochemical distribution of the antigen recognized by the c-Jun Ab-2 antibody was distinctly different from that of the other Jun proteins or mRNAs in the rat brain. This antibody (Ab-2) recognized a nuclear protein found extensively in the caudate-putamen, nucleus accumbens, layer II of the olfactory tubercle, the central nucleus of the amygdala, and the lateral division of the bed nucleus of the stria terminalis. Scattered labeled nuclei were found in a few other forebrain structures. Within the caudate-putamen, immunoreactivity was restricted to the matrix compartment, as determined by immunostaining of adjacent sections with the matrix-marker calbindin D28k. Western blots of caudate-putamen demonstrated that this antibody recognized a protein doublet of molecular masses approximately 37 and 34 kDa, distinct from the molecular masses of c-Jun, JunB and JunD. This unique neuroanatomical distribution and molecular mass suggests that this antibody recognizes a previously undescribed Jun-related antigen.

Animals↗
PubMed2002

Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor.

The regulation of c-Jun transcriptional activity by Jun N-terminal kinase (JNK) has become a paradigm for understanding how mitogen-activated protein (MAP) kinase signalling pathways elicit specific changes in gene transcription through selective phosphorylation of nuclear transcription factors. Selective phosphorylation of c-Jun by JNK is determined by a specific docking motif in c-Jun, the delta region, which enables JNK to associate physically with c-Jun. Analogous MAP kinase docking motifs have subsequently been found in several other transcription factors, indicating that this is a general mechanism for ensuring specificity of signal transduction. Genetic and biochemical studies in mice, flies and cultured cells have provided evidence that signals relayed by JNK through c-Jun regulate a range of cellular processes including cell proliferation, tumourigenesis, apoptosis and embryonic development. Despite these advances, in most cases, the genes or programs of gene expression downstream of JNK and c-Jun, which control these processes, have not been defined. Here, we review the current understanding of the molecular basis and biological consequences of JNK signalling via c-Jun and highlight some of the mechanistic issues, which remain to be resolved.

Animals↗
PubMed1999

Arachidonic acid induces mobilization of calcium stores and c-jun gene expression: evidence that intracellular calcium release is associated with c-jun activation.

Arachidonic acid (AA) plays a signaling role in the induction of several genes. We previously demonstrated that AA induces c-jun gene expression in the stromal cell line +/+.1 LDA 11 by a signaling pathway involving activation of the c-jun amino-terminal kinase (JNK). This study investigated the role of calcium in AA signaling of c-jun activation in +/+.1 LDA 11 cells. AA (10-50 microM) caused a rapid dose-dependent rise in cytosolic calcium. AA-induced calcium mobilization involved both influx of extracellular calcium and the release of intracellular calcium. The importance of calcium was investigated by variation of the extracellular calcium concentration, chelation of intracellular calcium and by calcium ionophore-induced influx of extracellular calcium. AA-induced c-jun gene expression and increased luciferase activity of a construct containing the high affinity AP-1 binding site was decreased in cells preincubated with the intracellular calcium chelator 1,2-bis(o-aminophenoxy)-eThane-N,N,N',N',-tetraacetic acid tetra(aceToxymethyl-esTer) (BAPTA-AM, 10 microM) prior to stimulation with AA. Similarly, chelation of intracellular calcium decreased AA-induced JNK activation. On the contrary, changes in the extracellular calcium concentration had no effect. Also, ionophore A23187 failed to induce c-jun and JNK activation either alone than in combination with AA. These results suggested that calcium was required for AA-dependent activation of c-jun, but that calcium alone was insufficient to induce activation of c-jun. Thus, release of calcium from intracellular stores is implicated in the signaling pathway of AA-induced c-jun activation in stromal cells.

Arachidonic Acid↗
PubMed2001

Control of the orientation of Fos-Jun binding and the transcriptional cooperativity of Fos-Jun-NFAT1 complexes.

Heterodimeric transcription regulatory proteins can bind to palindromic recognition elements in two opposite orientations. We have developed a gel-based fluorescence resonance energy transfer assay for quantifying heterodimer orientation preferences. Fos-Jun heterodimers bind in opposite orientations to AP-1 sites with different flanking sequences. The effects of individual amino acid and base pair substitutions on heterodimer binding orientation were quantified. Base pairs at positions +/-6 and +/-10 relative to the center of the AP-1 site were the principal determinants of Fos-Jun binding orientation. Amino acid residues of opposite charge adjacent to the basic regions of Fos and Jun had independent effects on heterodimer orientation. Exchange of these amino acid residues between the basic region-leucine zipper domains of Fos and Jun reversed the binding orientation. Heterodimers formed by full-length Fos and Jun exhibited the same changes in binding orientation in response to amino acid and base pair substitutions. The preferred orientation of heterodimer binding affected the stability of Fos-Jun-NFAT1 complexes at composite regulatory elements. Changes in heterodimer orientation preference altered the transcriptional activity and the promoter selectivity of Fos-Jun-NFAT1 complexes. Consequently, the orientation of Fos-Jun binding can influence transcriptional activity by altering cooperative interactions with other transcription regulatory proteins.

Amino Acid Sequence↗
PubMed2002

c-Jun regulates vascular smooth muscle cell growth and neointima formation after arterial injury. Inhibition by a novel DNA enzyme targeting c-Jun.

Neointima formation is a characteristic feature of common vascular pathologies, such as atherosclerosis and post-angioplasty restenosis, and involves smooth muscle cell proliferation. Determination of whether the bZIP transcription factor c-Jun plays a direct regulatory role in arterial lesion formation, or indeed in other disease, has been hampered by the lack of a potent and specific pharmacological inhibitor. c-Jun is poorly expressed in the uninjured artery wall and transiently induced following arterial injury in animal models. Here we generated a gene-specific DNAzyme-targeting c-Jun. We show that c-Jun protein is expressed in human atherosclerotic lesions. Dz13, a catalytically active c-Jun DNAzyme, cleaved c-Jun RNA and inhibited inducible c-Jun protein expression in vascular smooth muscle cells. Dz13 blocked vascular smooth muscle cell proliferation with potency exceeding its exact non-catalytic antisense oligodeoxynucleotide equivalent. Moreover, Dz13 abrogated smooth muscle cell repair following scraping injury in vitro and intimal thickening in injured rat carotid arteries in vivo. These studies demonstrate the positive influence on neointima formation by c-Jun and the therapeutic potential of a DNAzyme controlling its expression.

Animals↗
PubMed1992

Nuclear translocation of viral Jun but not of cellular Jun is cell cycle dependent.

The Jun protein is a transcription factor of the AP-1 complex, and it is concentrated in the cell nucleus. While the cellular Jun protein is transported into the nucleus in a cell-cycle-independent fashion, the oncogenic viral version of the protein translocates into the nucleus most rapidly during the G2 phase of the cell cycle and only slowly during G1 and S phases. This cell cycle dependence of nuclear transport has been mapped to the cysteine to serine mutation in the carboxyl-terminal portion of viral Jun. We have identified a complex nuclear translocation signal located in the basic region of viral Jun. This signal has the sequence ASKSRKRKL. A peptide of this sequence synthesized in vitro and conjugated to IgG can mediate cell-cycle-dependent translocation of the microinjected conjugate from the cytoplasm into the nucleus. The nuclear translocation signal has two functional domains. The pentapeptide RKRKL is sufficient as a cell-cycle-independent nuclear address. The entire signal is needed for cell-cycle-dependent nuclear translocation. The amino-terminal tetrapeptide contains the cysteine to serine substitution responsible for cell cycle dependence. Deletion analysis of the Jun protein suggests that the nuclear translocation signal identified in the basic region is required for nuclear translocation of Jun and may be the only such signal in the Jun molecule.

Amino Acid Sequence↗
PubMed2001

Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT).

The Jun N-terminal kinases (JNKs) recently have been shown to be required for thymocyte apoptosis and T cell differentiation and/or proliferation. To investigate the molecular targets of JNK signaling in lymphoid cells, we used mice in which the serines phosphorylated by JNK in c-Jun were replaced by homologous recombination with alanines (junAA mice). Lymphocytes from these mice showed no phosphorylation of c-Jun in response to activation stimuli, whereas c-Jun was rapidly phosphorylated in wild-type cells. Despite the fact that c-jun is essential for early development, junAA mice develop normally; however, c-Jun N-terminal phosphorylation was required for efficient T cell receptor-induced and tumor necrosis factor-alpha-induced thymocyte apoptosis. In contrast, c-Jun phosphorylation by JNK is not required for T cell proliferation or differentiation. Because jnk2-/- T cells display a proliferation defect, we concluded that JNK2 must have other substrates required for lymphocyte function. Surprisingly, jnk2-/- T cells showed reduced NF-AT DNA-binding activity after activation. Furthermore, overexpression of JNK2 in Jurkat T cells strongly enhanced NF-AT-dependent transcription. These results demonstrate that JNK signaling differentially uses c-Jun and NF-AT as molecular effectors during thymocyte apoptosis and T cell proliferation.

Animals↗
PubMed2002

c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons.

c-Jun is considered a major regulator of both neuronal death and regeneration. Stress in primary cultured CNS neurons induces phosphorylation of c-Jun serines 63 and 73 and increased c-Jun protein. However, total c-Jun N-terminal protein kinase (JNK) activity does not increase, and no satisfactory explanation for this paradox has been available. Here we demonstrate that neuronal stress induces strong activation of JNK2/3 in the presence of constitutively and highly active JNK1. Correspondingly, neurons from JNK1(-/-) mice show lower constitutive activity and considerably higher responsiveness to stress. p38 activity can be completely inhibited without effect on c-Jun phosphorylation, whereas 10 micrometer SB203580 strongly inhibits neuronal JNK2/3, stress-induced c-Jun phosphorylation, induced c-Jun activity, and neuronal death in response to trophic withdrawal stress. Neither constitutive JNK1 activity nor total neuronal JNK activity were significantly affected by this concentration of drug. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity.

Animals↗
PubMed1995

Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter.

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.

Activating Transcription Factor 2↗
PubMed1999

Expression of c-fos, c-jun, and c-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra.

The transcription factors c-fos and c-jun have been proposed to play a role in the initiation of programmed cell death in neurons. We have shown that programmed cell death, with the morphology of apoptosis, occurs in dopamine neurons of the substantia nigra (SN) during normal postnatal development and that this death event can be induced by early striatal target injury. We have investigated the relationship between c-fos and c-jun protein expression and induced death in neurons of the SN. Although c-fos is induced, it is unlikely to play a role in cell death, because its expression is not well correlated with apoptotic death either temporally or at a cellular level. Expression of c-jun, however, is both temporally and regionally correlated with induction of death, and, at a cellular level, it colocalizes with apoptotic morphology. The increased expression of c-jun is likely to be functionally significant, because it is associated with increased c-jun N-terminal kinase (JNK) and phosphorylated c-jun expression. JNK expression also colocalizes with apoptotic morphology. We conclude that c-jun is likely to play a role in the initiation of apoptotic cell death in these neurons.

Animals↗
PubMed1995

Complexes of p21RAS with JUN N-terminal kinase and JUN proteins.

RAS gene-encoded p21 protein has been found to increase in vitro phosphorylation of JUN via its kinase, JUN N-terminal kinase (JNK). This effect is mediated by increased phosphorylation of JNK in the presence of wild-type and oncogenic (Val-12) p21 protein in a dose-dependent manner. Oncogenic p21 protein is more potent in mediating this effect than its normal counterpart. Both normal and oncogenic p21 proteins bind to purified JNK and to JNK that is present in cell extracts from transformed fibroblasts and melanoma cells. Oncogenic and normal p21 proteins have also been found to bind to bacterially expressed JUN protein. This binding is dose dependent, enhanced by the presence of GTP, and depends on the presence of the first 89 amino acids of JUN (the delta domain), as it does not occur with v-jun. While the ability of both normal and oncogenic p21 proteins to bind JNK is strongly inhibited by a p21 peptide corresponding to aa 96-110, and more weakly inhibited by the p21 peptide corresponding to aa 115-126, p21-JUN interaction is inhibited by peptides corresponding to aa 96-110 and, to a lesser degree, by peptides corresponding to aa 35-47. The results suggest that the p21 protein interacts specifically with both JNK and JUN proteins.

3T3 Cells↗
PubMed1998

Impaired ionizing radiation-induced activation of a nuclear signal essential for phosphorylation of c-Jun by dually phosphorylated c-Jun amino-terminal kinases in ataxia telangiectasia fibroblasts.

The c-Jun amino-terminal kinases (JNKs) participate in intracellular signaling in response to cytokines and cellular stresses. JNKs are activated by phosphorylation on two critical residues, the threonine 183 and tyrosine 185, within the TPY motif. The activated JNKs, in turn, phosphorylate the nuclear protein c-Jun, a major component of the transcription factor AP1. In vitro studies have revealed a defect in ionizing radiation-induced activation of the JNK signaling pathway in lymphoblastoid cells from individuals with ataxia telangiectasia (AT). However, the biochemical basis for this signaling defect is not clear. Here, we show that ionizing radiation induces the phosphorylation of endogenous c-Jun in normal fibroblasts but not in AT fibroblasts. The p46 isoforms of dually phosphorylated JNKs were detected in the nuclei of both normal and AT fibroblasts following exposure to ionizing radiation or sham radiation. However, c-Jun kinase activity was detected in normal cells but not in AT cells. Furthermore, an exogenous purified active JNK protein was able to phosphorylate endogenous c-Jun in nuclear extracts only of normal cells and only after the cells were irradiated. Electrophoretic mobility shift assays also showed that the ionizing radiation-induced increase in the DNA binding activity of AP1 observed in normal cells was absent or markedly reduced in AT cell lines. These data suggest that the defect in ionizing radiation-induced signaling through c-Jun in AT cells is the result of impaired function of an unknown nuclear protein or proteins that negatively regulate both JNK and c-Jun.

Ataxia Telangiectasia↗
PubMed1992

Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression.

Myogenin and MyoD belong to a family of muscle-specific helix-loop-helix (HLH) proteins that have the potential to activate muscle-specific genes in nonmyogenic cells. Peptide growth factors can block the ability of myogenin and MyoD to activate their target genes. Here, we show that the growth factor-inducible proto-oncogenes c-fos, c-jun, and junB mimic the effects of exogenous growth factors and suppress trans-activation of the muscle creatine kinase (MCK) enhancer by myogenin and MyoD. In contrast, JunD, which shares DNA-binding specificity with JunB and c-Jun but is expressed constitutively in muscle cells, is an inefficient inhibitor of the trans-activating capacity of myogenin and MyoD. Transcriptional repression by Fos and Jun is specific to myogenic HLH proteins and is not observed with the widely expressed HLH protein E47, which recognizes the same DNA sequence. Repression of the MCK enhancer by Fos and Jun is targeted at the myogenin and MyoD DNA recognition sequence and can be mediated by the amino terminus of c-Jun. Comparison of several myogenin mutants for their responsiveness to Fos and Jun shows that repression is directed at the basic-HLH region. These results indicate that members of the Jun family can be distinguished on the basis of their effects on muscle-specific transcription and suggest there is cross talk between transcription factors that control myogenesis and those involved in cell proliferation.

Animals↗
PubMed2004

CD14- and toll-like receptor 4-dependent regulation of c-Fos, c-Jun and c-Jun phosphorylation in the adrenal gland after burn injury.

OBJECTIVES: Although the pathophysiology of the adrenocortical response after injury has been described, alterations in the molecular profile (e.g. transcription factors) of the adrenal gland itself are not well understood. The regulation of c-Fos, c-Jun, and c-Jun phosphorylation in the adrenal gland after burn injury was investigated in this study. In addition, since burn injury is often associated with lipopolysaccharide (LPS)-mediated sepsis, we examined the involvement of the LPS signaling pathway in the regulation of these transcription factors utilizing CD14 knockout and C3H/HeJ (encoding defective toll-like receptor 4) mice. METHODS: Adrenal glands harvested after an 18% total body surface area burn were subjected to RT-PCR and Western blot analyses of c-Jun and c-Fos. RESULTS: There was a rapid induction of c-Jun and c-Fos expression (mRNA and protein), and c-Jun serine phosphorylation. The induction of c-Jun and its phosphorylation after injury was greater in CD14 knockout and C3H/HeJ mice compared to their respective controls. A similar pattern was observed in the c-Fos regulation. CONCLUSIONS: These data suggest that c-Fos and c-Jun are activated in the adrenal gland in response to burn injury. In addition, an LPS-mediated signaling pathway may influence the regulation of these transcription factors after injury.

Adrenal Glands↗