Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is presented that the calcium-activated protease, calpain, is required for differentiation of 3T3-L1 preadipocytes into adipocytes induced by methylisobutylxanthine (a cAMP phosphodiesterase inhibitor), dexamethasone, and insulin. Calpain is expressed by preadipocytes and its level falls during differentiation. Exposure of preadipocytes to the calpain inhibitor N-acetyl-Leu-Leu-norleucinal or overexpression of calpastatin, a specific endogenous inhibitor of calpain, blocks expression of adipocyte-specific genes, notably the CCAAT/enhancer-binding protein (C/EBP)alpha gene, and acquisition of the adipocyte phenotype. The inhibitor disrupts the differentiation-inducing effect of methylisobutylxanthine (by means of the cAMP-signaling pathway), but is without effect on differentiation induced by dexamethasone or insulin. N-acetyl-Leu-Leu-norleucinal, or overexpression of calpastatin, inhibits reporter gene expression mediated by the C/EBPalpha gene promoter by preventing C/EBPbeta, a transcriptional activator of the C/EBPalpha gene, from binding to the promoter. These findings implicate calpain in the transcriptional activation of the C/EBPalpha gene, a process required for terminal adipocyte differentiation.
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PMID:Role of calpain in adipocyte differentiation. 999 15

Neurotransmitter-driven activation of transcription factors is important for control of neuronal and neuroendocrine functions. We show with an in vivo approach that the norepinephrine cAMP-dependent rhythmic hormone production in rat pineal gland is accompanied by a temporally regulated switch in the ratio of a transcriptional activator, phosphorylated cAMP-responsive element-binding protein (pCREB), and a transcriptional inhibitor, inducible cAMP early repressor (ICER). pCREB accumulates endogenously at the beginning of the dark period and declines during the second half of the night. Concomitant with this decline, the amount of ICER rises. The changing ratio between pCREB and ICER shapes the in vivo dynamics in mRNA and, thus, protein levels of arylalkylamine-N-acetyltransferase, the rate-limiting enzyme of melatonin synthesis. Consequently, a silenced ICER expression in pinealocytes leads to a disinhibited arylalkylamine-N-acetyltransferase transcription and a primarily enhanced melatonin synthesis.
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PMID:Transcription factors in neuroendocrine regulation: rhythmic changes in pCREB and ICER levels frame melatonin synthesis. 1021 92

In general, DNA-binding factors that activate gene transcription are thought to do so via reversible interaction with DNA. However, most studies, largely performed in vitro, suggest that the transcriptional activator, cAMP response element-binding protein (CREB), is exceptional in that it is constitutively bound to the promoter, where its phosphorylation leads to the recruitment of CREB-binding protein (CBP) to form a CREB/CBP/promoter complex. We have studied how CREB interacts with DNA in vivo to regulate the cAMP-responsive gene encoding human CRH (hCRH). Protein-DNA complexes were cross-linked in cells expressing the endogenous hCRH gene by exposure to a 10 nsec pulse of high-energy UV-laser light, followed by immunoaffinity purification of CREB-DNA complexes. Binding of CREB to a fragment of the hCRH promoter containing a canonical, functional cAMP response element was absent in untreated cells, but was specifically induced after activation of the protein kinase A pathway with forskolin. These data indicate that, in vivo, CREB, like the majority of other DNA-binding transcriptional activators, undergoes signal-mediated promoter interaction.
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PMID:Inducible binding of cyclic adenosine 3',5'-monophosphate (cAMP)-responsive element binding protein (CREB) to a cAMP-responsive promoter in vivo. 1031 17

Lanosterol 14alpha-demethylase (CYP51) produces MAS sterols, intermediates in cholesterol biosynthesis that can reinitiate meiosis in mouse oocytes. As a cholesterogenic gene, CYP51 is regulated by a sterol/sterol-regulatory element binding protein (SREBP)-dependent pathway in liver and other somatic tissue. In testis, however, cAMP/cAMP-responsive element modulator CREMtau-dependent regulation of CYP51 predominates, leading to increased levels of shortened CYP51 mRNA transcripts. CREM-/- mice lack the abundant germ cell-specific CYP51 mRNAs in testis while expression of somatic CYP51 transcripts is unaffected. The mRNA levels of squalene synthase (an enzyme preceding CYP51 in cholesterol biosynthesis in testis of CREM-/- mice are unchanged as compared with wild-type animals, showing that regulation by CREMtau is not characteristic for all cholesterogenic genes expressed during spermatogenesis. The -334/+314 bp CYP51 region can mediate both the sterol/SREBP-dependent as well as the cAMP/CREMtau-dependent transcriptional activation. SREBP-1a from somatic cell nuclear extracts binds to a conserved CYP51-SRE1 element in the CYP51 proximal promoter. The cAMP-dependent transcriptional activator CREMtau from germ cell nuclear extracts binds to a conserved CYP51-CRE2 element while no SREBP-1 binding is observed in germ cells. The two regulatory pathways mediating expression of CYP51 describe this gene as a cholesterogenic gene (SREBP-dependent expression in liver and other somatic cells) and also as a haploid expressed gene (CREMtau-dependent expression in haploid male germ cells). While in somatic cells all genes involved in cholesterol biosynthesis are regulated coordinately by the sterol/SREBP-signaling pathway, male germ cells contain alternate routes to control expression of cholesterogenic genes.
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PMID:Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. 1055 87

Heregulin beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 and human epidermal growth factor receptor 4 receptors, is a regulatory secretory polypeptide with distinct biological effects such as growth stimulation, differentiation, invasiveness, and migration in breast cancer cells. The mechanism underlying the diverse functions of HRG is not well established, but it is believed to be dependent on the induced changes in expression of specific cellular gene products, their modification, or both. The binding of basic leucine zipper transcription factors to the cAMP response element is known to activate a variety of gene products with a role or roles in growth regulation. In the studies presented here, we identified basic leucine zipper activating transcription factor (ATF) 4 as one of the HRG-inducible gene product. We demonstrated that HRG stimulation of human cancer cells induces expression of ATF4 mRNA and protein, ATF4 DNA binding activity, and ATF4 transactivating function. Consistent with its role as a transcriptional activator, HRG-stimulated ATF4 protein stimulated the transcription from an artificial promoter with three tandem ATF sites or from a naturally occurring promoter with ATF4 sites such as E-selectin. We also demonstrated a preferential role of the HRG-stimulated mitogen-activated protein kinase pathway, but not the phosphatidylinositol 3'-kinase pathway, in supporting the observed increase in ATF4 DNA binding activity and transcription from E-selectin promoter in HRG-stimulated cells. Because ATF4 binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that the stimulation of ATF4 expression and its transactivating functions may constitute an important mechanism of HRG-mediated regulation of putative genes with diversified functions. The present study is the first demonstration of regulation of expression and transactivation ability of ATF4 by any polypeptide growth factor.
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PMID:Heregulin induces expression, DNA binding activity, and transactivating functions of basic leucine zipper activating transcription factor 4. 1066 76

Yeast genes regulated by the transcriptional activator Yap1p were screened by two independent methods: (i) use of a LacZ-fused gene library and (ii) high-density membrane hybridization. Changes in transcriptome profile were examined in the presence and in the absence of Yap1p, as well as under normal and H2O2-mediated stress conditions. Both approaches gave coherent results, leading to the identification of many genes that appear to be directly or indirectly regulated by Yap1p. Promoter sequence analysis of target genes revealed that this regulatory effect is not always dependent upon the presence of a Yap1p binding site. The results show that the regulatory role of Yap1p is not restricted to the activation of stress response but that this factor can act as a positive or a negative regulator, both under normal and oxidative stress conditions. Among the targets, a few genes participating in growth control cascades were detected. In particular, the RPI1 gene, a repressor of the ras-cAMP pathway, was found to be downregulated by Yap1p during the early phase of growth, but upregulated in the stationary phase or after oxidative stress.
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PMID:A large-scale study of Yap1p-dependent genes in normal aerobic and H2O2-stress conditions: the role of Yap1p in cell proliferation control in yeast. 1084 71

The cell adhesion molecule melonoma cell adhesion molecule (MCAM)/MUC18/CD146 is specifically up-regulated on tumors of neuroectodermal origin and in animal models confers metastatic capacity to human melanoma cells. To identify critical regions regulating MCAM expression in melanomas, 1 kilobase of the MCAM 5' region was analyzed for promoter activity and transcription factor binding in 1 glioma, 1 carcinoma, and 4 melanoma cell lines. The minimal MCAM promoter (-106/+22 base pair (bp)) consists of 4 Sp-1 sites, two AP-2 elements, one cAMP responsive element, and the initiator surrounding the transcriptional start site. Analysis of mutated constructs indicated that the cAMP-responsive element is a major transcriptional activator in the majority of cell lines. Site-directed mutagenesis revealed that, in AP-2 expressing cells, the AP-2 site within the core promoter (-23 bp) has an inhibitory influence on MCAM expression while the AP-2 sites at -131 and -302 bp are activating. Functional AP-2 was observed in both MCAM positive and MCAM negative melanoma cell lines indicating that expression of MCAM does not require loss of this transcription factor. Furthermore, all MCAM constructs were strongly expressed in MCAM negative as well as MCAM positive cells, indicating that the expression of this gene is not controlled solely by the presence of transactivating factors binding to the investigated region.
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PMID:Identification of the elements regulating the expression of the cell adhesion molecule MCAM/MUC18. Loss of AP-2 is not required for MCAM expression in melanoma cell lines. 1093 73

The authors previously reported that one of the cAMP-response elements (CREs) of the human beta3-AR gene, beta3CRE2, interacts with a nuclear factor which is distinct from CREB/ATF family. We named this factor WATSF-1 (white adipose tissue specific factor-1) since it is preferentially expressed in WAT. In this work, we have shown the absence of DNA binding or transcriptional activity of this factor in several non-adipose cells tested. By computer analysis, beta3CRE2 was found to constitute an octameric element that is highly homologous to the binding site for some members of the nuclear hormone receptor superfamily. Using the response elements of other adipocyte-specific nuclear receptors as competitors, a 'cross-talk' between WATSF-1 and these response elements has been demonstrated. However, the affinity of WATSF-1 for these response elements differs from that for beta3CRE2 (self), implying that WATSF-1 is distinct from these adipocyte-specific nuclear receptors. Furthermore the DNA-binding activity of WATSF-1 was shown to be enhanced by phosphatase treatment, suggesting that phosphorylation may play an important role in the functional modulation of this factor. In an effort to prove that it is indeed an adipocyte-specific factor, we used 3T3-L1 cells, a cellular model of WAT, that can undergo differentiation into adipocytes. The DNA binding and transcriptional activity of this factor appeared during differentiation of the cells. Taken together, these results demonstrate that WATSF-1 is a putative white adipocyte-specific nuclear orphan receptor induced during adipogenesis and is a transcriptional activator through one of the CREs of the human beta3-AR gene. Targeting this factor may be a novel therapeutic approach to stimulation of the beta3-AR signal transduction pathway in adipose tissues.
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PMID:A putative white adipose tissue specific nuclear orphan receptor that interacts with the cAMP-response element of the human beta3-adrenergic receptor gene. 1094 Apr 87

cAMP signaling contributes to the control of the developmental progression of germ cells during the spermatogenic cycle. Genes regulated by cAMP include those encoding transcription factors such as the cAMP-responsive element modulator (CREM). The disruption of CREM gene expression in crem null mice results in arrest of spermatogenesis and infertility. The transcriptional control of the CREM gene is attributed to two promoters, P1 and P2. The P1 promoter constitutively activates the synthesis of messenger RNAs encoding activator (tau) and repressor (alpha) forms of CREM, whereas the cAMP-responsive P2 promoter activates the formation of messenger RNAs encoding the inducible cAMP early repressor. Here we report the identification of two additional promoters in the CREM gene, P3 and P4, that in the rat testis encode two novel transcriptional activator CREM isoforms, termed CREM theta1 and CREM theta2, respectively. Notably, the P3 and P4 promoters are activated by cAMP-dependent protein kinase, thereby providing cAMP-regulated transcription of CREM activators in addition to the established cAMP-regulated inducible cAMP early repressor. Analysis ex vivo of CREM gene expression in temporally staged segments of the seminiferous tubule during the spermatogenic cycle shows that the activities of the P1, P3, and P4 promoters are independently regulated. Our identification of the cAMP-activated P3 and P4 promoters that direct expression of the novel theta1 and theta2 activator isoforms of CREM brings further insight into the complex expression of the CREM gene during germ cell development and may have implications in understanding the control of fertility.
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PMID:Novel cyclic adenosine 3',5'-monophosphate (cAMP) response element modulator theta isoforms expressed by two newly identified cAMP-responsive promoters active in the testis. 1108 20

The molecular mechanism by which cAMP activates the rat phenylethanolamine N-methyltransferase (PNMT) gene was examined by transient transfection of the wild-type rat PNMT promoter-luciferase reporter gene construct pGL3RP893 into PC12 cells. Forskolin treatment (10 microM) of the transfected cells for 3--6 h maximally induced luciferase threefold. Induction by forskolin was mimicked by the cAMP analog, 8-Br-cAMP, and prevented in PC12 cells pretreated with the protein kinase A (PKA) inhibitor H-89 or co-transfected with an expression construct for PKI, a polypeptide inhibitor of PKA. Furthermore, forskolin did not activate the PNMT promoter when the 893 bp PNMT promoter-reporter gene construct was transfected into the PKA-deficient cell line, A126. Detailed examination of the forskolin responsiveness of PNMT constructs harboring > or = 60 bp and < 893 bp of PNMT promoter demonstrated that the cAMP-responsive element(s) lay between < 392 bp and > or =60 bp. Within this region of the promoter lies a functional binding element for Egr-1, a transcriptional activator of the PNMT gene. Forskolin treatment of PC12 cells also rapidly increased nuclear levels of Egr-1 and the catalytic subunit of PKA (PKA-C), with the rise in PKA-C preceding that of Egr-1. Mutation of the --165 bp Egr-1 site markedly decreased forskolin activation of the PNMT promoter. These findings demonstrate that the rat PNMT gene promoter can be activated via the cAMP-PKA signal transduction pathway, mediated by the immediate early gene transcription factor, Egr-1.
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PMID:Role of Egr-1 in cAMP-dependent protein kinase regulation of the phenylethanolamine N-methyltransferase gene. 1125 3


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