Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian transcription factor AP-2 is a retinoic acid inducible sequence-specific DNA-binding protein that is developmentally regulated. In this report, the functional domains necessary for AP-2 DNA binding were studied. AP-2 required a dimerization domain and an adjacent region of net basic charge to achieve a sequence-specific protein:DNA interaction. The sequences responsible for dimerization consisted of two putative amphipathic alpha helices separated by a large intervening span region. This helix-span-helix (HSH) domain was unable to bind DNA when separated from the basic region, but was still capable of dimerization. The ability of the HSH domain to function as a module that promotes DNA binding through dimerization was further demonstrated by attaching it to the heterologous basic region of the c-Jun proto-oncogene product. The resulting chimeric protein specifically recognized an AP-1 DNA-binding site in the absence of an intact c-Jun leucine repeat and in a manner that was dependent on the presence of a functional AP-2 dimerization domain.
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PMID:Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins. 199 22

The mouse embryonal carcinoma cell line F9 differentiates in vitro in a manner analogous to the formation of extraembryonic (parietal or visceral) endoderm from inner cell mass cells in early embryogenesis. After retinoic acid addition to cells in monolayer culture, differentiation to parietal endoderm proceeds over several days. Early changes in gene expression are seen before differentiation becomes irreversible, and may be mediated post-transcriptionally. Midway through differentiation, transcription of a group of endogenous and exogenous (viral) genes rises. Increased activity of the DNA-binding transcription factor AP-1 has been implicated in this rise in transcription, but it has not been determined whether this is the only factor involved. In the third phase of differentiation, a group of proteins characteristic of parietal endoderm appears. The F9 cell system may be significant in being among the first in which altered transcription factor activity responsible for changing gene expression during differentiation is understood.
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PMID:Gene expression and differentiation in F9 mouse embryonal carcinoma cells. 261 60

Induction of differentiation of F9 teratocarcinoma stem cells by retinoic acid and cAMP has been shown to involve the activation of the transcription factor AP-1 (a heterodimer of the proto-oncogene products c-Fos and c-Jun); moreover, stable expression of either Fos or Jun drives F9 cells into differentiation. Phorbol ester tumor promoters and short-wave-length ultraviolet (uv) irradiation are efficient inducers of AP-1 activity in various differentiated cells, but it has been shown that phorbol esters do not induce AP-1 activity in undifferentiated F9 cells. We examine here whether uv irradiation induces AP-1 activity in these cells and drives F9 cells into differentiation. We show that uv induces, in contrast to phorbol esters, the formation of active AP-1 by activating transcription from the c-jun gene. Ultraviolet-induced AP-1 drives transcription from AP-1-dependent promoters coding for differentiation-associated proteins (such as urokinase and keratin 18). However, in uv-treated cells, these genes are activated earlier and to a greater extent than in cells treated with retinoic acid and cAMP. More importantly, uv, in contrast to retinoic acid and cAMP, does not induce the accumulation of collagen alpha 1 (IV) and laminin B1 RNA. Our data suggest that the c-jun gene in F9 cells is accessible to immediate activation, but that uv-induced AP-1 activation does not suffice to induce the full program of F9 cell differentiation.
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PMID:Ultraviolet irradiation, although it activates the transcription factor AP-1 in F9 teratocarcinoma stem cells, does not induce the full complement of differentiation-associated genes. 752 41

The differentiation of both embryonal carcinoma (EC) and embryonic stem (ES) cells can be triggered in culture by exposure to retinoic acid and results in the transcriptional induction of both the endogenous mouse keratin 18 (mK18) intermediate filament gene and an experimentally introduced human keratin 18 (K18) gene as well as a variety of other markers characteristic of extraembryonic endoderm. The induction of K18 in EC cells is limited, in part, by low levels of ETS and AP-1 transcription factor activities which bind to sites within a complex enhancer element located within the first intron of K18. RNA levels of ETS-2, c-Jun, and JunB increase upon the differentiation of ES cells and correlate with increased expression of K18. Occupancy of the ETS site, detected by in vivo footprinting methods, correlates with K18 induction in ES cells. In somatic cells, the ETS and AP-1 elements mediate induction by a variety of oncogenes associated with the ras signal transduction pathway. In EC cells, in addition to the induction by these limiting transcription factors, relief from negative regulation is mediated by three silencer elements located within the first intron of the K18 gene. These silencer elements function in F9 EC cells but not their differentiated derivatives, and their activity is correlated with proteins in F9 EC nuclei which bind to the silencers and are reduced in the nuclei of differentiated F9 cells. The induction of K18, associated with the differentiation of EC cells to extraembryonic endoderm, is due to a combination of relief from negative regulation and activation by members of the ETS and AP-1 transcription factor families.
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PMID:AP-1, ETS, and transcriptional silencers regulate retinoic acid-dependent induction of keratin 18 in embryonic cells. 752 51

We have examined the 5'-flanking region (944 bp) of the human choline acetyltransferase (hChAT) gene for sequences that modulate its transcriptional activity and identified a sequence 5'-TGACCCA-3' which confers c-Jun/c-Fos (AP-1) inducibility of homologous and heterologous promoters. Using transient transfections in neuroblastoma NE-1-115 and COS-1 cells, we show that ligand-activated estrogen receptor (HEGo) represses the transcriptional activation by c-Fos/c-Jun. Testing HEGo mutants in transfection assays reveals that the ligand-binding domain is crucial for this repression, whereas the N-terminal (A/B) region and the DNA-binding domain are not essential. Gel retardation assays show that the hChAT AP-1 recognition sequence binds in vitro baculovirus-produced c-Jun/c-Fos proteins. This binding is inhibited by addition of baculovirus-produced HEGo. In contrast to HEGo, ligand-activated glucocorticoid, androgen, and retinoic acid receptors (RARs) enhance the transcription activation induced by c-Jun/c-Fos. All three types of RARs--RAR alpha, beta, gamma--and RXR alpha are able to stimulate AP-1 activity on the proximal hChAT promoter. Several mechanism possibilities involving protein-protein interaction are discussed to explain the phenomena.
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PMID:Positive and negative effects of nuclear receptors on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter. 774 8

Retinoic acid receptors (RARs) regulate gene expression either by directly binding to the RAR-responsive elements or by antagonizing the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis, rheumatoid arthritis and in tumor metastases. We demonstrate here that synthetic retinoids inhibit 12-O-tetradecanoylphorbol-14-acetate-induced transcription from the stromelysin AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR beta and RAR gamma, but not for RAR alpha, in transactivation assays, are able to inhibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it should be possible to develop retinoids that are completely specific for AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and AP1 antagonism functions of RARs.
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PMID:Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. 782 31

F9 teratocarcinoma is a useful model for studying early embryogenesis since these cells can differentiate into primitive or parietal endoderm under the influence of retinoic acid or retinoic acid and cyclic AMP, respectively. We have found that three isoforms of protein kinase C (PKC alpha, -beta, and -gamma) were expressed in undifferentiated stem cells. When the cells were treated with retinoic acid either alone or in the presence of cAMP for 120 h, PKC alpha mRNA and protein levels increased, whereas those of PKC beta and PKC gamma became undetectable. These changes began within 24 h of drug treatment and were complete by 48-72 h. In order to determine the functional significance of the induction of PKC alpha during F9 differentiation, we established two stable transfectants that overexpressed PKC alpha protein between 4- and 5-fold compared to wild type cells. Characterization of these cell lines revealed an altered pattern of expression of some of the markers of F9 differentiation. The clone that had the highest amount of PKC alpha protein constitutively expressed mRNA for type IV collagen and c-Jun, which are not normally expressed until 24-48 h of treatment with differentiation agents. In the other overexpressing clone, these markers were induced much faster than in wild type cells. The growth rate of both overexpressing clones was less than wild type cells, while the expression of the PKC beta protein in these clones was similar to the levels found in differentiated F9 cells. However, other markers of differentiation, including the cellular morphology and levels of pST6-135 and c-myc RNA, responded to agents identically in both wild type and PKC-alpha-overexpressing clones. Therefore, overexpression of PKC alpha is not sufficient to induce full differentiation of F9 cells. However, our data suggest that certain pathways that lead to the expression of differentiation-dependent genes are regulated by PKC alpha protein levels.
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PMID:Characterization of conventional protein kinase C (PKC) isotype expression during F9 teratocarcinoma differentiation. Overexpression of PKC alpha alters the expression of some differentiation-dependent genes. 796 96

Fusion gene constructs containing the human choline acetyltransferase 5' flanking region are stimulated by thyroid hormone (T3) in neuronal NG108-15 and NE1-115 cells but not in non neuronal COS-1 and JEG-3 cells. To identify potential T3 receptor binding elements (T3RE), chimeric plasmids containing various lengths of the 5' end of the hChAT gene linked to the CAT reporter gene were assayed by transient transfections into NG108-15, NE1-115 and COS-1 cells. We show that regulation is T3 specific as estrogen, dexamethasone, dihydrotestosterone, all-trans-retinoic acid and 9-cis-retinoic acid have no effect. We localized several potential T3REs and characterized the most proximal T3RE (position 3280-3291) which contains two hexameric half-sites arranged as a direct repeat without a base pair spacer. An oligonucleotide containing this sequence confers T3 responsiveness to a heterologous promoter. The transcriptional response of this T3RE is markedly reduced after mutation of the first or second half-site indicating that both half-sites are required for a maximal T3 response. We have found that RAR alpha, RXR alpha and COUP-TF do not enhance T3 responsiveness and therefore they may not interact with T3R alpha in NG108-15 cells on this regulatory sequence. T3R monomer and dimer specific binding to the proximal T3RE is demonstrated by gel-retardation DNA binding assays and by methylation interference experiments. In COS-1 cells, T3R inhibits transcriptional activation by the transcription factor AP-1 whereas in NE1-115 cells T3R enhances AP-1 mediated activation in a T3 dependant fashion. It is likely that these effects involve protein-protein interactions. These results suggest that the T3 receptor can act as a positive transcriptional regulatory factor on the hChAT gene.
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PMID:Trans-activation by thyroid hormone receptors of the 5' flanking region of the human ChAT gene. 805 82

The binding of transcription factor AP-1 and vitamin D receptor (VDR) to the composite AP-1 plus vitamin-D-responsive promoter region (AP-1 + VDRE) of the human osteocalcin gene was characterized in osteocalcin-producing (MG-63) and non-producing (U2-Os, SaOs-2) human osteosarcoma cell lines. In mobility-shift assays with AP-1 + VDRE, AP-1, and VDRE probes and nuclear extracts from these cells, one AP-1-specific and two VDR-specific (fast and slow mobility) interactions were observed. Characterization of the complexes indicated that AP-1 and VDR do not bind simultaneously to the AP-1 + VDRE oligonucleotide. Intensity of the complexes was greatly influenced by cell density: in MG-63 and SaOs-2 cells, AP-1 binding was strong during the proliferative period disappearing at confluency whereas, in U2-Os cells, AP-1 binding was prominent also at the confluent stage. Furthermore, MG-63 cells possessed the faster migrating VDR complex at all stages of confluency whereas, in U2-Os and SaOs-2 cells, it was very weak or absent. There were no detectable differences in the levels of VDR protein between these cell lines. In U2-Os cells, the level of c-jun mRNA was higher than in the other two cell lines, whereas none of these cell lines exhibited detectable levels of c-fos mRNA at the confluent stage. Exogenous c-Jun protein effectively blocked the VDR-DNA interaction. Further, all these cell lines expressed mRNA for retinoid X receptor alpha (RXR alpha), the factor suggested to be required for the VDR-DNA interaction. The presence of an accessory factor in the VDR-DNA complexes was indirectly shown by treatment of the cells with 9-cis retinoic acid and by cycloheximide. Both treatments reduced VDR binding without affecting the VDR protein level. These results suggest that AP-1 interferes with VDR binding to the AP-1 + VDRE element and that the vitamin D responsiveness of the osteocalcin gene correlates with weak AP-1 binding and strong binding of the faster migrating VDR complex.
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PMID:Functional interference between AP-1 and the vitamin D receptor on osteocalcin gene expression in human osteosarcoma cells. 807 31

Vitamin A derivatives (retinoids) affect a large variety of fundamental biological processes. Understanding of the signaling mechanism has been greatly advanced by the cloning of specific retinoid receptors. These regulatory proteins belong to the steroid/thyroid hormone nuclear receptor superfamily. Two types of retinoid receptors have been identified, the retinoic acid receptors (RAR alpha, beta and gamma) and the retinoid X receptors (RXR alpha, beta, and gamma). Similar to the steroid hormone receptors, the retinoid receptors bind to specific DNA sequences that have diad symmetries. However, the RARs require heterodimerization with RXRs for efficient DNA binding and gene regulation, while the RXRs can bind to DNA and function as homodimers in the presence of 9-cis-retinoic acid. In addition, RXRs can form heterodimers with thyroid hormone receptors and the vitamin D3 receptor and other receptors. Thus the RXRs have a very central role in serving as a partner for several hormone and vitamin receptors and thus may allow cross talk between different hormone signals. Retinoid responses can be restricted by the COUP-TF orphan receptors which bind to overlapping DNA sequences. Besides the classical way of action via DNA binding, the retinoid receptors can also interfere with other signaling pathways by interacting with the transcription factor AP-1. The advances made in understanding the mechanism of action of retinoids promise to contribute to the understanding and control of physiological responses and diseases.
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PMID:Signal transduction by retinoid receptors. 814 16


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