Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor activator of nuclear factor-kappaB ligand (RankL) is a potent osteoclastogenic cytokine the expression of which is regulated at the transcriptional level by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], protein kinase A (PKA) activators such as PTH and transmembrane glycoprotein 130 (gp130)-activating cytokines such as oncostatin M. We recently identified five highly conserved chromatin domains located significant distances upstream of the RankL transcriptional start site that contribute to the ability of 1,25-(OH)2D3 and its receptor to enhance RankL gene output. We therefore screened these five common regulatory regions for their potential ability to mediate the actions of PKA- and gp130-activators using a directed chromatin immunoprecipitation approach employing antibodies to the PKA target cAMP response element-binding protein (CREB) and the gp130 target signal transducer and activator of transcription 3. CREB was identified at each of the upstream regulatory regions; signal transducer and activator of transcription 3, in contrast, was associated with only a subset. Interestingly, only the most distal of these regions demonstrated CREB- and oncostatin M-regulated transcriptional activity in a heterologous transfection system. Mapping studies pointed to two highly conserved cAMP response elements as well as an adjacent regulatory site that bound Runt transcription factor 2 and was able to influence both basal as well as hormone-inducible RankL activity. Surprisingly, PKA and gp130 activation prompted recruitment of RNA polymerase II to the five distal enhancers as well as to the RankL transcriptional start site. Activation was also accompanied by a significant and location-selective rise in histone 4 acetylation. This study demonstrates that the activation of RankL gene expression by PKA- and gp130-inducers is mediated via common regulatory domains that also served to facilitate the activity of 1,25-(OH)2D3.
Mol Endocrinol 2007 Jan
PMID:Transcriptional control of receptor activator of nuclear factor-kappaB ligand by the protein kinase A activator forskolin and the transmembrane glycoprotein 130-activating cytokine, oncostatin M, is exerted through multiple distal enhancers. 1705 39

Transcription of the cytochrome P450 17 (CYP17) gene is regulated by cAMP-dependent binding of steroidogenic factor-1 (SF-1) to its promoter in the adrenal cortex. Using temporal chromatin immunoprecipitation and mammalian two-hybrid experiments, we establish the reciprocal presence of coactivators [general control nonderepressed (GCN5), cAMP response element-binding protein-binding protein, p300, p300/cAMP response element-binding protein-binding protein CBP associated factor, p160s, polypyrimidine tract associated splicing factor, and p54(nrb)], corepressors (class I histone deacetylases, receptor interacting protein, nuclear receptor corepressor, and Sin3A), and SWI/SNF (human homolog of yeast mating type switching/sucrose nonfermenting) and imitation SWI chromatin remodeling ATPases on the CYP17 promoter during transcription cycles in the H295R adrenocortical cell line. A ternary GCN5/SRC-1/SF-1 complex forms on the CYP17 promoter with cAMP-dependence within 30 min of cAMP stimulation, and corresponds with SWI/SNF chromatin remodeling. This complex is sensitive to the SF-1 antagonist sphingosine and results in decreased transcription of CYP17. GCN5 acetyltransferase activity and carboxy terminus binding proteins alternatively mediate disassembly of the complex. This work establishes the temporal order of cAMP-induced events on the promoter of a key steroidogenic gene during SF-1-mediated transcription.
Mol Endocrinol 2007 Feb
PMID:Coregulator exchange and sphingosine-sensitive cooperativity of steroidogenic factor-1, general control nonderepressed 5, p54, and p160 coactivators regulate cyclic adenosine 3',5'-monophosphate-dependent cytochrome P450c17 transcription rate. 1712 66

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
Mol Pharmacol 2007 Mar
PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41

Protein kinase Cepsilon (PKCepsilon) plays a pivotal role in cardioprotection during cardiac ischemia and reperfusion injury. Recent studies demonstrated that prenatal cocaine exposure caused a decrease in PKCepsilon expression and increased heart susceptibility to ischemic injury in adult offspring, suggesting an in utero programming of PKCepsilon gene expression pattern in the heart. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for cocaine-mediated repression of the PKCepsilon gene in the heart. Pregnant rats were administered either saline or cocaine intraperitoneally (15 mg/kg) twice daily from days 15 to 20 of gestational age, and term fetal hearts were studied. Cocaine treatment significantly decreased PKCepsilon mRNA and protein levels in the heart. CpG dinucleotides found in cAMP response element-binding protein (CREB), CREB/c-Jun1, and CREB/c-Jun2 binding sites at the proximal promoter region of the PKCepsilon gene were densely methylated and were not affected by cocaine. In contrast, methylation of CpGs in the activator protein 1 (AP-1) binding sites was low but was significantly increased by cocaine. Reporter gene assays showed that the AP-1 binding site played a strong stimulatory role of PKCepsilon gene transcription. Methylation of the AP-1 binding sites significantly decreased AP-1 binding to the PKCepsilon promoter. Supershift analyses implicated c-Jun homodimers binding to the AP-1 binding sites. Cocaine did not affect nuclear c-Jun levels or the binding of c-Jun to the unmethylated AP-1 binding sites. The results indicate a role for DNA methylation in cocaine-mediated PKCepsilon gene repression in the developing heart and suggest an epigenetic mechanism affecting this gene linked with vulnerability of ischemic injury in the heart of adult offspring.
Mol Pharmacol 2007 May
PMID:Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart. 1730 99

Histone acetylation is a highly dynamic posttranslational modification that plays an important role in gene expression. Previous work showed that promoter histone deacetylation is accompanied by progesterone receptor (PR)-mediated activation of the mouse mammary tumor virus (MMTV) promoter. We investigated the role of this deacetylation and found that this histone deacetylation is not a singular event. In fact, histone acetylation at the MMTV promoter is highly dynamic, with an initial increase in acetylation followed by an eventual net deacetylation of histone H4. The timing of increase in acetylation of H4 coincides with the time at which PR, RNA polymerase II, and histone acetyltransferases cAMP response element-binding protein (CREB)-binding protein and p300 are recruited to the MMTV promoter. The timing in which histone H4 deacetylation occurs (after PR and RNA polymerase II recruitment) and the limited effect that trichostatin A and small interfering RNA knockdown of histone deacetylase (HDAC)3 have on MMTV transcription suggests that this deacetylation activity is not required for the initiation of PR-mediated transcription. Interestingly, two HDACs, HDAC1 and HDAC3, are already present at the MMTV before transcription activation. HDAC association at the MMTV promoter fluctuates during the hormone treatment. In particular, HDAC3 is temporarily undetected at the MMTV promoter within minutes after hormone treatment when the histone H4 acetylation increases but returns to the promoter near the time when histone acetylation levels start to decline. These results demonstrate the dynamic nature of coactivator/corepressor-promoter association and histone modifications such as acetylation during a transcription activation event.
Mol Endocrinol 2007 Apr
PMID:Dynamic histone acetylation/deacetylation with progesterone receptor-mediated transcription. 1722 84

The glutamate receptor adaptor protein Homer is concentrated in the postsynaptic density of excitatory synapses and is critical for normal operation of synaptic transmission. In this study, we investigated the responsiveness of Homer family proteins to dopamine stimulation with the psychostimulant cocaine in rat striatal neurons both in vivo and in vitro. We found that a single dose of cocaine specifically induced a rapid and transient increase in protein levels of the Homer1a, but not Homer1b/c and Homer2a/b, isoforms in the striatum. This selective Homer1a induction was mediated primarily through activation of dopamine D1, but not D2, receptors. Both protein kinase A and Ca(2+)/calmodulin-dependent protein kinases are important for mediating the cocaine stimulation of Homer1a expression. At the transcriptional level, cAMP response element-binding protein serves as a prime transcription factor transmitting the signals derived from D1 receptors and associative pathways to the CaCRE sites within the Homer1a promoter. From a functional perspective, non-cross-linking Homer1a, once induced, competed with the cross-linking isoforms of Homer proteins (Homer1b/c and Homer2a/b) to uncouple the connection of group I metabotropic glutamate receptors (mGluRs) with inositol-1,4,5-triphosphate receptors. These results indicate that cocaine possesses the ability to stimulate Homer1a expression in striatal neurons through a specific synapse-to-nucleus pathway. Moreover, inducible Homer1a expression may represent a transcription-dependent mechanism underlying the dynamic regulation of submembranous macromolecular complex formation between group I mGluRs and their anchoring proteins.
Mol Pharmacol 2007 Apr
PMID:In vivo regulation of Homer1a expression in the striatum by cocaine. 1723 98

We have demonstrated previously that brain-derived neurotrophic factor (BDNF) signaling in the amygdala is required for the consolidation of fear memory. This study is designed to characterize the signal cascades by which fear conditioning modulates transcriptional and translational expression of BDNF. Real-time reverse transcription-coupled polymerase chain reaction showed a significant increase in BDNF exon I- and III-containing mRNA in the amygdala of fear-conditioned rats, indicating that fear conditioning was capable of up-regulating BDNF mRNA. Bilateral administration of actinomycin D or anisomycin to the amygdala attenuated conditioning-induced increase in BDNF protein. Inhibitors for N-methyl-d-aspartate (NMDA) receptor, L-type voltage-dependent calcium channel (L-VDCC), adenylyl cyclase, cAMP-dependent protein kinase (PKA), and calcium/calmodulin-dependent kinase IV (CaMKIV) significantly reduced the increase. Moreover, DNA affinity precipitation and chromatin immunoprecipitation assays showed that phosphorylated cAMP response element-binding protein (p-CREB) binding activity in the proximal region of BDNF promoter I and III was significantly increased after fear conditioning. Intra-amygdala administration of cAMP response element decoy DNA before training impaired fear learning. Taken together, these results suggest that calcium influx through NMDA receptors and L-VDCCs during fear conditioning activates PKA and CaMKIV resulting in CREB phosphorylation. The phosphorylated CREB binds to BDNF promoter and up-regulates the expression of BDNF in the amygdala, which helps the consolidation of fear memory.
Mol Pharmacol 2007 Aug
PMID:Transcriptional regulation of brain-derived neurotrophic factor in the amygdala during consolidation of fear memory. 1745 85

Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) by TNF-alpha contributes to the pathogenesis of hypoglycemia in endotoxin shock. In this study, the molecular mechanism underlying the inhibition was investigated in hepatoma cells (rat H4IIE and human HepG2). PEPCK expression was induced by cAMP, and the induction was reduced by TNF-alpha at protein and mRNA levels in H4IIE cells. The inhibition was observed in the PEPCK gene promoter in a PEPCK-luciferase reporter. Activation of nuclear factor kappaB (NF-kappaB) pathway was required for the transcriptional inhibition of PEPCK gene. Degradation of NF-kappaB inhibitor (IkappaB) and p65 nuclear translocation were involved in the inhibition. An interaction of histone deacetylase 3 (HDAC3) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT) with the PEPCK gene promoter was induced by TNF-alpha and observed in a chromatin immunoprecipitation assay. The TNF-induced inhibition was blocked by HDAC inhibitor or HDAC3 knockdown. The blocking effect was also observed in knockdown of corepressor SMRT. Point mutation suggests that cAMP response element (CRE) is required for TNF-induced inhibition of the PEPCK gene promoter. Phosphorylation of cAMP response element-binding protein at Ser133 and expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha were not changed by TNF-alpha in H4IIE cells. The transcriptional activity of CRE-binding protein was inhibited by TNF-alpha in a CRE-luciferase reporter. The data suggests that the nuclear corepressor proteins of HDAC3 and SMRT mediate TNF inhibition of PEPCK transcription. The inhibition mechanism is related to activation of NF-kappaB and inhibition of CRE-binding protein activity by the corepressor. These data suggest a novel activity of nuclear corepressor in the regulation of PEPCK expression by TNF-alpha.
Mol Endocrinol 2007 Jul
PMID:Nuclear corepressor is required for inhibition of phosphoenolpyruvate carboxykinase expression by tumor necrosis factor-alpha. 1745 89

The biological role of 1,25-dihydroxyvitamin D(3) has generally been related to calcium homeostasis, but this hormone also has fundamental effects on processes of cellular proliferation and differentiation. The genomic actions of 1,25-dihydroxyvitamin D(3) are mediated by the vitamin D receptor (VDR) present in target cells. However, VDR transcriptional regulation is not well understood, probably attributable to the complexity of the VDR gene and its promoter. In the present study, it is demonstrated that administration of the pituitary transcription factor Pit-1 (originally found in the pituitary gland but also present in other nonpituitary cell types and tissues) to the MCF-7 (human breast adenocarcinoma) cell line induces a significant increase in VDR mRNA and protein levels. Conversely, Pit-1-targeted small interference RNA markedly reduced expression of VDR in MCF-7 cells. Reporter gene assays demonstrated that the effect of Pit-1 is mediated by its binding to a region located between -254 and -246 bp from the VDR transcription start site. Selective mutations of this site completely abolished VDR transcription. Chromatin immunoprecipitation analysis showed that binding of Pit-1 to the VDR promoter leads additionally to recruitment of cAMP response element-binding protein binding protein, acetylated histone H4, and RNA polymerase II. Surprisingly, Pit-1 binding also recruits VDR protein to the VDR promoter. Using several cell lines with different levels of VDR expression, it was demonstrated that up-regulation of VDR transcription by Pit-1 is dependent on the presence of VDR protein, suggesting that transcriptional expression of VDR in a given cell type is dependent on, among other factors, its own expression levels.
Mol Endocrinol 2007 Jul
PMID:Cellular expression levels of the vitamin D receptor are critical to its transcriptional regulation by the pituitary transcription factor Pit-1. 1745 92

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in synaptic plasticity. In this issue of Molecular Pharmacology, Ou and Gean (p. 350) thoroughly describe the molecular cascade by which fear learning leads to an increase in BDNF expression in the lateral amygdala (LA). Calcium influx through N-methyl-D-aspartate receptors and L-type voltage-dependent calcium channels, which occurs in the LA during fear conditioning, activates protein kinase A and Ca2+/calmodulin-dependent protein kinase IV. Each induces phosphorylation of cAMP response element-binding protein, which binds to the BDNF promoter, leading to BDNF expression in the LA, and contributes to fear memory consolidation.
Mol Pharmacol 2007 Aug
PMID:Brain-derived neurotrophic factor: linking fear learning to memory consolidation. 1752 82


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