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

Activated estrogen receptor alpha (ERalpha) modulates transcription triggered by the transcription factor activator protein-1 (AP-1), which consists of Jun-Jun homodimers and Jun-Fos heterodimers. Previous studies have demonstrated that the interference occurs without binding of ERalpha to DNA but probably results from protein.protein interactions. However, involvement of a direct interaction between ERalpha and AP-1 is still debated. Using glutathione S-transferase pull-down assays, we demonstrated that ERalpha bound directly to c-Jun and JunB but not to FOS family members, in a ligand-independent manner. The interaction could occur when c-Jun was bound onto DNA, as shown in a protein-protein-DNA assay. It implicated the C-terminal part of c-Jun and amino acids 259-302 present in the ERalpha hinge domain. ERalpha but not an ERalpha mutant deleted of amino acids 250-303 (ER241G), also associated with c-Jun in intact cells, in the presence of estradiol, as shown by two-hybrid and coimmunoprecipitation assays. We also show that ERalpha, c-Jun, and the p160 coactivator GRIP1 can form a multiprotein complex in vitro and in intact cells and that the ERalpha.c-Jun interaction could be crucial for the stability of this complex. VP16-ERalpha and c-Jun, which both interact with GRIP1, had synergistic effect on GAL4-GRIP1-induced transcription in the presence of estradiol, and this synergistic effect was not observed with the ERalpha mutant VP16-ER241G or when c-Fos, which bound GRIP1 but not ERalpha, was used instead of c-Jun. Finally, ER241G was inefficient for regulation of AP-1 activity, and an ERalpha truncation mutant encompassing the hinge domain had a dominant negative effect on ERalpha action. These results altogether demonstrate that ERalpha can bind to c-Jun in vitro and in intact cells and that this interaction, by stabilizing a multiprotein complex containing p160 coactivator, is likely to be involved in estradiol regulation of AP-1 responses.
 ...
PMID:Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. 1147 71

Sensitivity to glucocorticoid (GC)-evoked apoptosis in lymphoid cell lines correlates closely with GC-mediated suppression of c-Myc expression. To establish a functional role for c-Myc in GC-mediated apoptosis, we have stably expressed MycER(TM), the human c-Myc protein fused to the modified ligand-binding domain of the murine estrogen receptor alpha, in GC-sensitive CEM-C7-14 cells. In CEM-C7-14 cells, MycER(TM) constitutively imparts c-Myc functions. Cells expressing MycER(TM) (C7-MycER(TM)) exhibited a marked reduction in cell death after 72 h in 100 nM dexamethasone (Dex), with 10-20-fold more viable cells when compared to the parental CEM-C7-14 clone. General GC responsiveness was not compromised, as evidenced by Dex-mediated suppression of endogenous c-Myc and cyclin D3, and induction of c-Jun and the glucocorticoid receptor. MycER(TM) also blunted Dex-mediated upregulation of p27(kipI) and suppression of the Myc target p53. In comparison to parental CEM-C7-14 cells, Dex-evoked DNA strand breaks were negligible and caspase activation was delayed, but the extent of G1 cell cycle arrest was similar in C7-MycER(TM) cells. Myc-ER(TM) did not result in permanent, complete resistance to GC however, and the GC-treated cells eventually died, indicative of redundant or interactive mechanisms in the GC-evoked lytic response of lymphoid cells. Our results emphasize the importance of c-Myc suppression in GC-evoked apoptosis of CEM-C7-14 cells.
 ...
PMID:Constitutive expression of ectopic c-Myc delays glucocorticoid-evoked apoptosis of human leukemic CEM-C7 cells. 1149 86

We previously reported that enhanced transcriptional activation of estrogen receptor alpha (ERalpha) contributed to [(12)Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERalpha by a dominant negative mutant of ERalpha (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G(0)/G(1), subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent up-regulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERalpha in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERalpha-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.
 ...
PMID:Contribution of estrogen receptor alpha to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway. 1178 7

Transcriptional activation of the cyclin D1 gene (CCND1) plays a pivotal role in G(1)-phase progression, which is thereby controlled by multiple regulatory factors, including nuclear receptors (NRs). Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated. We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor alpha complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent. This process coincides with the release from the same DNA region of a transcriptional repressor complex including Yin-Yang 1 (YY1) and histone deacetylase 1 and is sufficient to induce the assembly of the basal transcription machinery on the promoter and to lead to initial cyclin D1 accumulation in the cell. Later on in estrogen stimulation, the cyclin D1/Cdk4 holoenzyme associates with the CCND1 promoter, where E2F and pRb can also be found, contributing to the long-lasting gene enhancement required to drive G(1)-phase completion. Interestingly, progesterone triggers similar regulatory events through its own NRs, suggesting that the gene regulation cascade described here represents a crossroad for the transcriptional control of G(1)-phase progression by different classes of NRs.
 ...
PMID:Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. 1528 24

We investigated the mechanisms by which estrogen alters insulin signaling in 3T3-L1 adipocytes. Treatment with 17beta-estradiol (E2) did not affect insulin-induced tyrosine phosphorylation of insulin receptor. E2 enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1/p85 association, phosphorylation of Akt, and 2-deoxyglucose uptake at 10(-8) m, but inhibited these effects at 10(-5) m. A concentration of 10(-5) m E2 enhanced insulin-induced phosphorylation of IRS-1 at Ser(307), which was abolished by treatment with a c-Jun NH(2)-terminal kinase inhibitor. In addition, the effect of E2 was abrogated by pretreatment with a specific estrogen receptor antagonist, ICI182,780. Membrane-impermeable E2, E2-BSA, did not affect the insulin-induced phosphorylation of Akt at 10(-8) m, but inhibited it at 10(-5) m. Furthermore, E2 decreased the amount of estrogen receptor alpha at the plasma membrane at 10(-8) m, but increased it at 10(-5) m. In contrast, the subcellular distribution of estrogen receptor beta was not altered by the treatment. These results indicate that E2 affects the metabolic action of insulin in a concentration-specific manner, that high concentrations of E2 inhibit insulin signaling by modulating phosphorylation of IRS-1 at Ser(307) via a c-Jun NH(2)-terminal kinase-dependent pathway, and that the subcellular redistribution of estrogen receptor alpha in response to E2 may explain the dual effect of E2.
 ...
PMID:Altered subcellular distribution of estrogen receptor alpha is implicated in estradiol-induced dual regulation of insulin signaling in 3T3-L1 adipocytes. 1626 59

The critical role of polyamines in cell growth has led to the development of a number of agents that interfere with polyamine metabolism including a novel class of polyamine analogues, oligoamines. Here we demonstrate that oligoamines specifically suppress the mRNA and protein expression of estrogen receptor alpha (ERalpha) and ERalpha target genes in ER-positive human breast cancer cell lines, whereas neither ERbeta nor other steroid hormonal receptors are affected by oligoamines. The constitutive expression of a cytomegalovirus promoter-driven exogenous ERalpha in ER-negative MDA-MB-231 human breast cancer cells was not altered by oligoamines, suggesting that oligoamines specifically suppress ERalpha transcription rather than affect mRNA or protein stability. Further analysis demonstrated that oligoamines disrupted the DNA binding activity of Sp1 transcription factor family members to an ERalpha minimal promoter element containing GC/CA-rich boxes. Treatment of MDA-MB-231 cells with the JNK-specific inhibitor SP600125 or expression of the c-Jun dominant negative inhibitor TAM67 blocked the oligoamine-activated JNK/c-Jun pathway and enhanced oligoamine-inhibited ERalpha expression, suggesting that AP-1 is a positive regulator of ERalpha expression and that oligoamine-activated JNK/AP-1 activity may antagonize the down-regulation of ERalpha induced by oligoamines. Taken together, these results suggest a novel antiestrogenic mechanism for specific polyamine analogues in human breast cancer cells.
 ...
PMID:Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. 1667 12

Insulin like growth factor I (IGF-I) displays estrogenic activity in breast cancer cells. This activity is strictly dependent on the presence of estrogen receptor alpha (ERalpha). However the precise molecular mechanisms involved in this process are still unclear. IGF-I treatment induces phosphorylation of the AF1 domain of ERalpha and activation of estrogen regulated genes. These genes are characterized by important differences in promoter architecture and response element composition. We show that promoter structure is crucial for IGF-I-induced transcription activation. We demonstrate that on a complex promoter such as the pS2/TFF1 promoter, which contains binding sites for ERalpha and for the activating protein-1 (AP1) complex, transcriptional activation by IGF-I requires both ERalpha and the AP1 complex. IGF-I is unable to stimulate transcription of an estrogen-regulated gene under the control of a minimal promoter containing only a binding site for ERalpha. We propose a molecular mechanism with stepwise assembly of the AP1 complex and ERalpha during transcription activation of pS2/TFF1 by IGF-I. IGF-I stimulation induces rapid phosphorylation and an increase in protein levels of the AP1 complex. Binding of the phosphorylated AP1 complex to the pS2/TFF1 promoter allows recruitment of the chromatin remodeling factor Brg1 followed by binding of ERalpha via its interaction with c-Jun.
 ...
PMID:Estrogen receptor alpha and the activating protein-1 complex cooperate during insulin-like growth factor-I-induced transcriptional activation of the pS2/TFF1 gene. 1731 69

The somatostatin receptor subtype 2 (sst2) mediates inhibition of hormone secretion and cell proliferation, and modulates neurotransmission. Its expression is widespread in various normal tissues and many malignant cells, and is up-regulated by estrogen in breast cancer cells. This study was undertaken to investigate molecular mechanism of transcriptional regulation of the human sst2 gene, for which an additional exon (exon 1) in the 5'-untranslated region was recently found. Transient transfection and mutational analysis showed that the immediate 5'-upstream region containing two Sp1 (-54/-45 and -88/-79) and an ATF/CRE (-69/-62) sites provided full promoter activity. An EMSA together with transfection analysis in Sp1-deficient Drosophila Schneider line (SL2) cells showed that Sp1 acted on the proximal Sp1 site, whereas Sp3, Sp1, and Sp2 did on the distal Sp1 site. Activating transcription factor-2 (ATF)-2, c-Jun, and cyclic AMP response element-binding protein (CREB) interacted with the ATF/CRE site. Transcriptional activation by estrogen occurred through two different regions; one included these proximal elements and the other existed in the upstream region containing estrogen response element (ERE) half-site (-348/-344) and GC-rich sequence (-447/-414). This upstream estrogen responsiveness was observed in a human breast cancer T47D cell, but not in GH(3) or estrogen receptor alpha (ERalpha) -expressing HeLa cells, and was potentiated by overexpression of ERalpha or ERbeta, whose binding to the ERE half-site was verified by EMSAs. A chromatin immunoprecipitation assay suggested that ERalpha was recruited to the ERE half-site after estrogen treatment in T47D cells. The present results should provide a molecular basis for transcriptional regulation in a variety of physiological and pathological contexts of sst2-expressing tissues.
 ...
PMID:Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation. 1823 10

Estrogen-responsive genes often have an estrogen response element (ERE) positioned next to activator protein-1 (AP-1) binding sites. Considering that the interaction between ERE and AP-1 elements has been described for the modulation of bone-specific genes, we investigated the 17-beta-estradiol responsiveness and the role of these cis-elements present in the F promoter of the human estrogen receptor alpha (ERalpha) gene. The F promoter, containing the sequence analyzed here, is one of the multiple promoters of the human ERalpha gene and is the only active promoter in bone tissue. Through electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP), and re-ChIP assays, we investigated the binding of ERalpha and four members of the AP-1 family (c-Jun, c-fos, Fra-2, and ATF2) to a region located approximately 800 bp upstream of the transcriptional start site of exon F of the human ERalpha gene in SaOS-2 osteoblast-like cells. Reporter gene assay experiments in combination with DNA binding assays demonstrated that F promoter activity is under the control of upstream cis-acting elements which are recognized by specific combinations of ERalpha, c-Jun, c-fos, and ATF2 homo- and heterodimers. Moreover, ChIP and re-ChIP experiments showed that these nuclear factors bind the F promoter in vivo with a simultaneous occupancy stimulated by 17-beta-estradiol. Taken together, our findings support a model in which ERalpha/AP-1 complexes modulate F promoter activity under conditions of 17-beta-estradiol stimulation.
 ...
PMID:ERalpha and AP-1 interact in vivo with a specific sequence of the F promoter of the human ERalpha gene in osteoblasts. 1824 70

Estradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these "genomic effects", estrogen may also act as a more general "trophic factor" triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with beta-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates beta-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of beta-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS).
 ...
PMID:Estradiol activates beta-catenin dependent transcription in neurons. 1936 Jan 3


1 2 Next >>