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)

Methamphetamine (METH) is a psychostimulant that can cause long-lasting neurodegenerative effects in humans and animals. These toxic effects appear to occur, in part, via activation of dopamine (DA) D1 receptors. This paper assessed the possibility that the DA D1 receptor antagonist, SCH23390, might inhibit METH-induced changes in the expression of several members of immediate early genes (IEGs) which are known to control more delayed expression of other genes. We found that injections of METH (4x10 mg/kg, given at 2 h intervals) caused significant increases in c-fos and fra-2 expression which lasted from 30 min to 4 h. Pre-treatment with SCH23390, given 30 min before each METH injection, completely blocked METH-induced expression of c-fos, but only partially inhibited fra-2 mRNA expression. These results were confirmed by Western blot analysis which showed METH-induced changes in c-Fos protein expression that were blocked by pretreatment with SCH23390. There were also delayed METH-induced DA D1 receptor-dependent effects on fosB mRNA expression. Even though fra-1 expression was not affected by pretreatment with METH alone, the repeated injections of SCH23390 caused substantial decreases in fra-1 mRNA expression in both the presence and absence of METH. The repeated injections of METH caused no changes in the mRNAs for c-jun, junB or junD. However, there were significant increases in the phosphorylation of c-Jun protein (ser63). Phosphorylation of c-Jun occurred in a delayed fashion (16 and 24 h after the last METH injections) and was attenuated by SCH23390 pretreatment. Interestingly, SCH23390 given alone caused significant decreases in phospho-c-Jun at all time-points. The METH injections also caused delayed induction in the expression of members of the Egr family of transcription factors in a DA D1 receptor-dependent fashion. Repeated injections of SCH23390 caused substantial suppression of basal striatal egr-1 and egr-2 mRNA expression but not of that of egr-3. Both crem and arc mRNA levels were induced by METH in a SCH23390-sensitive fashion. Moreover, multiple injections of SCH23390 given alone caused marked inhibition of basal arc expression. These results show that multiple injections of METH can differentially affect the expression of several IEGs, some of which occurred in a DA D1 receptor dependent fashion. The SCH23390-mediated suppression of basal fra-1, egr-1, and egr-2 mRNA levels suggests that their basal expression in the striatum might be dependent on tonic stimulation of the DA D1 receptor.
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PMID:Differential effects of methamphetamine and SCH23390 on the expression of members of IEG families of transcription factors in the rat striatum. 2005 87

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by sequence-specific targeting of multiple mRNAs. Although lineage-, maturation-, and disease-specific miRNA expression has been described, miRNA-dependent phenotypes and miRNA-regulated signaling in hematopoietic cells are largely unknown. Combining functional genomics, biochemical analysis, and unbiased and hypothesis-driven miRNA target prediction, we show that lentivirally over-expressed miR-125b blocks G-CSF-induced granulocytic differentiation and enables G-CSF-dependent proliferation of murine 32D cells. In primary lineage-negative cells, miR-125b over-expression enhances colony-formation in vitro and promotes myelopoiesis in mouse bone marrow chimeras. We identified Stat3 and confirmed Bak1 as miR-125b target genes with approximately 30% and 50% reduction in protein expression, respectively. However, gene-specific RNAi reveals that this reduction, alone and in combination, is not sufficient to block G-CSF-dependent differentiation. STAT3 protein expression, DNA-binding, and transcriptional activity but not induction of tyrosine-phosphorylation and nuclear translocation are reduced upon enforced miR-125b expression, indicating miR-125b-mediated reduction of one or more STAT3 cofactors. Indeed, we identified c-Jun and Jund as potential miR-125b targets and demonstrated reduced protein expression in 32D/miR-125b cells. Interestingly, gene-specific silencing of JUND but not c-JUN partially mimics the miR-125b over-expression phenotype. These data demonstrate coordinated regulation of several signaling pathways by miR-125b linked to distinct phenotypes in myeloid cells.
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PMID:Enforced expression of miR-125b affects myelopoiesis by targeting multiple signaling pathways. 2136 88

Activator protein-1 (AP-1) regulates a wide range of cellular processes including proliferation, differentiation, and apoptosis. As a transcription factor, AP-1 is commonly found as a heterodimer comprised of c-Jun and c-Fos proteins. However, other heterodimers may also be formed. The function of these dimers, specifically the heterodimeric AP-1 comprised of JunD and c-Fos (AP-1(JunD/c-Fos)), has not been elucidated. Here, we identified a function of AP-1(JunD/c-Fos) in Xenopus hematopoiesis. A gain-of-function study performed by overexpressing junD and c-fos and a loss-of-function study using morpholino junD demonstrate a critical role for AP-1(JunD/c-Fos) in hematopoiesis during Xenopus embryogenesis. Additionally, we confirmed that JunD of AP-1(JunD/c-Fos) is required for BMP-4-induced hematopoiesis. We also demonstrated that BMP-4 regulated JunD activity at the transcriptional regulation and post-translational modification levels. Collectively, our findings identify AP-1(JunD/c-Fos) as a novel hematopoietic transcription factor and the requirement of AP-1(JunD/c-Fos) in BMP-4-induced hematopoiesis during Xenopus hematopoiesis.
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PMID:The role of heterodimeric AP-1 protein comprised of JunD and c-Fos proteins in hematopoiesis. 2282 70


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