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)

Chemically induced differentiation of Friend murine erythroleukemia cells (F-MELC) is a multistep process with a latent period of about 12 h preceding irreversible commitment to terminal maturation. To gain understanding of the early genetic response of F-MELC to the dimethyl sulfoxide (DMSO) inducer of F-MELC differentiation, we have investigated by Northern blot analysis the expression of fos and jun family genes that encode components of the transcription factor AP-1 complex. Our results show that c-jun mRNA is not detected at any time in untreated and DMSO-treated F-MELC. In contrast, DMSO-induced differentiation of F-MELC is associated with an early and transient induction of c-fos and junB mRNAs by 2 to 8 h treatment while in presence of dexamethasone, an inhibitor of F-MELC commitment, c-fos mRNA is not detected and junB mRNA remains at basal levels. junD mRNA is detected at low levels in untreated F-MELC and remains unchanged during DMSO treatment. Furthermore, DMSO treatment in a F-MELC cell line resistant to DMSO-differentiation does not result in an early induction of c-fos and junB mRNAs. Taken together, these results indicate that the DMSO-induced F-MELC differentiation is accompanied by an early co-induction of c-fos and junB during the latent period preceding the commitment to erythroid maturation.
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PMID:Co-induction of c-fos and junB during the latent period preceding commitment of Friend erythroleukemia cells to differentiation. 151 4

We have studied the expression of the c-jun gene during dimethyl-sulfoxide (DMSO) induced differentiation of Friend erythroleukemia (F-MEL) cells. No expression of c-jun was detected in a differentiation-competent F-MEL cell line (745A) either before or after treatment with DMSO. By contrast, c-jun expression was constitutive in a F-MEL cell line (TFP10) resistant to DMSO-induced differentiation and increased with DMSO. We have investigated the possible role of c-jun in conferring this resistance by stably transfecting either sense or antisense c-jun constructs into both differentiation-sensitive 745A and defective TFP10 cell lines. Inhibition of c-jun expression by antisense transcripts in the TFP10 cells restored their ability to undergo erythroid differentiation when exposed to DMSO while expression of junB or junD antisense vectors failed to do so. In addition, c-jun overexpression in the 745A cells resulted in decreased DMSO-induced differentiation. These results indicate a correlation between the level of c-jun expression and the ability of F-MEL cells to undergo DMSO-induced differentiation and suggest that c-Jun may be an important negative regulator in this process.
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PMID:Antisense c-jun overcomes a differentiation block in a murine erythroleukemia cell line. 820 42

Tumor promoter 12-O-tetradecanoylphorbol-13-acetate stimulates an increase in erythroid differentiation activity in human fibrosarcoma HT1080 cells. Here, we demonstrate that this process involves a rapid accumulation of five species of activin beta A/erythroid differentiation factor mRNA, followed by protein kinase C activation, and that variation in size of the activin transcripts is due to multiple 3' ends, presumably reflecting an alternative polyadenylation. In transiently transfected HT1080 cells, a 97-bp DNA fragment containing an AP-1 consensus sequence (TGAGTCA) located in the 3'-flanking region of the activin gene was capable of activating the heterologous herpes simplex virus thymidine kinase (tk) and SV40 early promoters, and a cotransfected c-Jun enhanced these fusion promoter activities. The deletion of TGAG sequences from the AP-1 element in the 97-bp DNA sequence context abolished its c-Jun-mediated activation from the tk promoter even in HT1080 cells overexpressing stably transfected c-Jun. Cotransfected adenovirus E1A products repressed the tk promoter activity enhanced by the activin AP-1 element itself or in concert with transiently transfected c-Jun, indicating that the putative AP-1 sequence acts as an activator element, depending upon c-Jun activity. These results suggest that the 3'-flanking DNA sequences of the human activin beta A subunit gene play an important role in its expression.
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PMID:Possible roles of the 3'-flanking sequences of the human activin beta A subunit gene in its expression. 848 45

Previously, we elucidated the role of bone morphogenetic protein 4 (BMP-4) in the dorsal-ventral patterning of the Xenopus embryo by using a dominant negative mutant of the BMP-4 receptor (DN-BR). The present paper describes the involvement of Ras, Raf, and activator protein 1 (AP-1) in BMP-4 signaling during Xenopus embryonic development. The AP-1 activity was determined by injecting an AP-1-dependent luciferase reporter gene into two-cell-stage Xenopus embryos and measuring the luciferase activity at various developmental stages. We found that injection of BMP-4 mRNA increased AP-1 activity, whereas injection of DN-BR mRNA inhibited AP-1 activity. Similar inhibitory effects were seen with injection of mRNAs encoding dominant negative mutants of c-Ha-Ras, c-Raf, or c-Jun. These results suggest that the endogenous AP-1 activity is regulated by BMP-4/Ras/Raf/Jun signals. We next investigated the effects of Ras/Raf/AP-1 signals on the biological functions of BMP-4. DN-BR-induced dorsalization of the embryo, revealed by the formation of a secondary body axis or dorsalization of the ventral mesoderm explant analyzed by histological and molecular criteria, was significantly reversed by coinjection of [Val12]Ha-Ras, c-Raf, or c-Jun mRNA. Furthermore, the BMP-4-stimulated erythroid differentiation in the ventral mesoderm was substantially inhibited by coinjection with the dominant negative c-Ha-Ras, c-Raf, or c-Jun mutant. Our results suggest the involvement of Ras/Raf/AP-1 in the BMP-4 signaling pathway.
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PMID:Involvement of Ras/Raf/AP-1 in BMP-4 signaling during Xenopus embryonic development. 857 Jun 44

High-level globin expression in erythroid precursor cells depends on the integrity of NF-E2 recognition sites, transcription factor AP-1-like protein-binding motifs, located in the upstream regulatory regions of the alpha- and beta-globin loci. The NF-E2 transcription factor, which recognizes these sites, is a heterodimer consisting of (i) p45 NF-E2 (the larger subunit), a hematopoietic-restricted basic leucine zipper protein, and (ii) a widely expressed basic leucine zipper factor, p18 NF-E2, the smaller subunit. p18 NF-E2 protein shares extensive homology with the maf protooncogene family. To determine an in vivo role for p18 NF-E2 protein we disrupted the p18 NF-E2-encoding gene by homologous recombination in murine embryonic stem cells and generated p18 NF-E2-/- mice. These mice are indistinguishable from littermates throughout all phases of development and remain healthy in adulthood. Despite the absence of expressed p18 NF-E2, DNA-binding activity with the properties of the NF-E2 heterodimer is present in fetal liver erythroid cells of p18 NF-E2-/- mice. We speculate that another member of the maf basic leucine zipper family substitutes for the p18 subunit in a complex with p45 NF-E2. Thus, p18 NF-E2 per se appears to be dispensable in vivo.
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PMID:Complexity of the erythroid transcription factor NF-E2 as revealed by gene targeting of the mouse p18 NF-E2 locus. 862 68

The E26 and avian erythroblastosis virus (AEV) avian retroviruses induce acute leukemia in chickens. E26 can block both erythroid and myeloid differentiation at an early multipotent stage. Moreover, E26 can block erythroid differentiation at the erythroid burst-forming unit/erythroid CFU (BFU-E/CFU-E) stage, which also corresponds to the differentiation stage blocked by AEV. AEV carries two oncogenes, v-erbA and v-erbB, whereas E26 encodes a single 135-kDa Gag-Myb-Ets fusion oncoprotein. v-ErbA is responsible for the erythroid differentiation arrest through negative interferences with both the retinoic acid receptor (RAR) and the thyroid hormone receptor (T3R/c-ErbA). We investigated whether Myb-Ets could block erythroid differentiation in a manner similar to v-ErbA. We show here that Myb-Ets inhibits both RAR and c-ErbA activities on specific hormone response elements in transient-expression assays. Moreover, Myb-Ets abrogates the inactivation of transcription factor AP-1 by RAR and T3R, another feature shared with v-ErbA. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to retinoic acid and T3. Analysis of a series of mutants of Myb-Ets reveals that the domains of the oncoprotein involved in these inhibitory activities are the same as those involved in oncogenic transformation of hematopoietic cells. These data demonstrate that the Myb-Ets oncoprotein shares properties with the v-ErbA oncoprotein and that inhibition of ligand-dependent RAR and c-ErbA functions by Myb-Ets is responsible for blocking the differentiation of hematopoietic progenitors.
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PMID:Myb-Ets fusion oncoprotein inhibits thyroid hormone receptor/c-ErbA and retinoic acid receptor functions: a novel mechanism of action for leukemogenic transformation by E26 avian retrovirus. 888 63

We have reported previously that antisense c-jun overcomes a block of Friend erythroleukemia cells to differentiation suggesting that the factor c-Jun may be an important negative regulator of erythroid differentiation. The recently described erythroid transcription factor NF-E2 plays an important role in the regulation of the transcription of globin genes and recognizes a sequence containing an AP-1 site. NF-E2 is a complex of two bZip proteins, p45 and p18/Maf. In order to determine whether c-Jun can interact with NF-E2/AP-1 sites to regulate transcriptional activation from them, we have compared the activity of AP-1 and NF-E2 in transient transcriptional assays, in erythroid and nonerythroid cells in the presence of c-jun sense and antisense expression vectors. In non-erythroid cells, c-Jun activates and NF-E2p18 inhibits both AP-1 and NF-E2 activities, suggesting that NF-E2/AP-1 sites function as AP-1 binding sites in these cells. In contrast, NF-E2p18 is a positive regulator of NF-E2 activity in erythroid cells. c-Jun alone is also a positive regulator of NF-E2 activity in erythroid cells but in association with NF-E2p18 inhibits this activity. Moreover antisense c-jun increases endogenous NF-E2 activity in erythroid cells. These results suggest that c-Jun could act as a repressor of NF-E2 transcriptional activity by forming inactive c-Jun/NF-E2p18 heterocomplexes which interfer with the transcription of globin genes in Friend erythroleukemia cells.
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PMID:c-Jun inhibits NF-E2 transcriptional activity in association with p18/maf in Friend erythroleukemia cells. 904 95

The erythroleukemia-inducing Friend spleen focus-forming virus (SFFV) encodes a unique envelope glycoprotein which allows erythroid cells to proliferate and differentiate in the absence of erythropoietin (Epo). In an attempt to understand how the virus causes Epo independence, we have been studying signal transduction pathways activated by Epo to determine if SFFV exerts its biological effects by constitutively activating any of these pathways in the absence of Epo. We previously demonstrated that Stat proteins, the downstream components of the Epo-induced Jak-Stat pathway, are constitutively activated in SFFV-infected cells. In this study, we demonstrate that SFFV also activates Raf-1, MEK and mitogen-activated protein (MAP) kinase, the downstream components of the Raf-1/MAP kinase pathway. This pathway was activated in cells infected with the polycythemia-inducing strain of SFFV, which induces both proliferation and differentiation of erythroid cells in the absence of Epo, as well as in cells infected with the anemia-inducing strain of the virus, which still require Epo for differentiation. Inhibition of Raf-1 by using antisense oligonucleotides led to a partial inhibition of the Epo-independent proliferation of SFFV-infected cells. Expression of the transcription factors c-Jun and JunB, but not c-Fos, was induced in SFFV-infected cells in the absence of Epo, suggesting that constitutive activation of the Raf-1/MAP kinase pathway by the virus may result in deregulation of AP-1 activity. We conclude from our studies that infection of erythroid cells with SFFV leads to the constitutive activation of signal transduction molecules in both the Jak-Stat and Raf-1/MAP kinase pathways and that both of these pathways must be activated to achieve maximum proliferation and differentiation of erythroid cells in the absence of Epo.
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PMID:Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway. 944 83

The effect of modulating AP-1 activity on the levels of induced erythroid and megakaryocytic differentiation of the erythroleukemia cell line K562 was examined. Cells were stably transfected with expression vectors encoding either a tetracycline-responsive dominant negative c-Jun (JunDN) or a hybrid Raf protein inducible by estrogen. Down-regulation of AP-1 activity by induction of JunDN enhanced erythroid differentiation by two agents, cytosine arabinoside and activin A. Induction of AP-1 activity by elevated Raf activity inhibited erythroid differentiation, thus mimicking the well-known effect of tetradecanoyl phorbol acetate (TPA) on this process. Induced Raf activity also brought about partial megakaryocytic differentiation of the line. However, inhibition of TPA-induced AP-1 activity by induction of JunDN gave mixed results. While the cytological effects of TPA treatment observed on cytochemical staining were inhibited by JunDN, two protein markers for megakaryocytic differentiation were increased. These results, while supportive of current models of hematopoietic lineage-specific gene expression, suggest a complex and temporal mechanism of lineage commitment.
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PMID:AP-1 activity affects the levels of induced erythroid and megakaryocytic differentiation of K562 cells. 958 20

The transcription factor AP1 has been implicated in the induction of apoptosis in cells in response to stress factors and growth factor withdrawal. We report here that AP1 is necessary for the induction of apoptosis following hormone withdrawal in the erythropoietin (EPO)-dependent erythroid cell line HCD57. AP1 DNA binding activity increased upon withdrawal of HCD57 cells from EPO. A dominant negative AP1 mutant rendered these cells resistant to apoptosis induced by EPO withdrawal and blocked the downregulation of Bcl-XL. JunB is a major binding protein in the AP1 complex observed upon EPO withdrawal; JunB but not c-Jun was present in the AP1 complex 3 h after EPO withdrawal in HCD57 cells, with a concurrent increase in junB message and protein. Furthermore, analysis of AP1 DNA binding activity in an apoptosis-resistant subclone of HCD57 revealed a lack of induction in AP1 DNA binding activity and no change in junB mRNA levels upon EPO withdrawal. In addition, we determined that c-Jun and AP1 activities correlated with EPO-induced proliferation and/or protection from apoptosis. AP1 DNA binding activity increased over the first 3 h following EPO stimulation of HCD57 cells, and suppression of AP1 activity partially inhibited EPO-induced proliferation. c-Jun but not JunB was present in the AP1 complex 3 h after EPO addition. These results implicate AP1 in the regulation of proliferation and survival of erythroid cells and suggest that different AP1 factors may play distinct roles in both triggering apoptosis (JunB) and protecting erythroid cells from apoptosis (c-Jun).
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PMID:AP1 regulation of proliferation and initiation of apoptosis in erythropoietin-dependent erythroid cells. 963 52


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