UNIPROT:P61278 - FACTA Search

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cAMP-responsive element (CRE) and its cognate transcription factor CREB can mediate induction of gene transcription in response to membrane depolarization and calcium influx. In this study, the effect of cyclosporin A (CsA) and FK506 on depolarization-induced glucagon gene transcription was investigated in a pancreatic islet cell line by transfection of reporter fusion genes. CsA and FK506 inhibited depolarization-induced glucagon gene transcription, FK506 being more potent than CsA. CsA/FK506 responsiveness was mediated by the glucagon CRE and also by well characterized CREs of the choriogonadotropin and somatostatin genes. Rapamycin antagonized the inhibitory effect of FK506 but not CsA, suggesting that FK506 and CsA may act through complex formation with distinct intracellular immunophilins. Overexpression of calcineurin, which is known to be inhibited by drug-immunophilin complexes, rendered pancreatic islet cells more resistant to the inhibitory effects of CsA and FK506. These results demonstrate an inhibition by CsA and FK506 of CRE-mediated, calcium-induced transcription and suggest that membrane depolarization relies on calcineurin phosphatase activity for activation of CREB/CRE-mediated gene transcription. The interference with CRE-mediated gene transcription represents a novel mechanism of CsA/FK506 action, which may underlie pharmacological effects and toxic manifestations of these potent immunosuppressive drugs.
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PMID:Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization. 769 84

Cytochrome P450c17, 17 alpha-hydroxylase/17,20 lyase, is a key enzyme in the steroidogenic pathway leading to the production of corticosteroids and androgens from the adrenal gland and sex steroids from the gonads. Both enzymatic activities of the protein are encoded by a single gene, CYP17, which is expressed in both the human adrenal and gonad but not in the placenta, and in the rodent gonad and placenta but not the rodent adrenal. We isolated and sequenced a full-length rat genomic clone (7,553 bases) containing the entire coding region of the rat P450c17 gene, and all intronic sequences and 1,560 bp of 5'-flanking DNA (EMBL Acc#X69816). To determine which sequences in the rat P450c17 promoter may be responsible for basal and cAMP-stimulated gene transcription, deletion constructs containing between -1,560 and -53 base pairs of 5'-flanking DNA from the rat P450c17 gene were ligated to plasmids expressing the reporter gene luciferase and transfected into two mouse cell lines, adrenal Y-1 cells, and testicular Leydig MA-10 cells. Highest basal and cAMP-stimulated luciferase activity were found in constructions containing 156 bp of 5'-flanking DNA. This construction contains a sequence very similar to the consensus cis element reported to be responsible for cAMP enhancement of the rat somatostatin gene and also overlaps a sequence similar to the consensus element for the orphan steroid receptor SF-1. Gel mobility-shift analysis, using a 30-bp oligonucleotide containing this region incubated with cellular extracts from cultured mouse adrenal Y-1 and mouse Leydig MA-10 cells, revealed all the extracts to contain two proteins that bind to this sequence. Neither DNA-protein complex was further retarded by co-incubation with an anti-CREB antibody, suggesting that cAMP regulation of this gene occurs via a non-CREB protein. Mutation of this oligonucleotide resulted in loss of binding of only one of these proteins, but resulted in loss of both basal and cAMP stimulation of rat P450c17 promoter-regulated gene transcription. Southwestern analysis suggests that one of these proteins is larger than SF-1. This study suggests that a protein that binds to an SF-1 like sequence regulates both basal and cAMP-stimulated rat P450c17 gene expression in rodent cells.
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PMID:Transcriptional regulation of rat cytochrome P450c17 expression in mouse Leydig MA-10 and adrenal Y-1 cells: identification of a single protein that mediates both basal and cAMP-induced activities. 770 52

The X gene product encoded by the hepatitis B virus, termed pX, is a promiscuous transactivator of a variety of viral and cellular genes under the control of diverse cis-acting elements. Although pX does not appear to directly bind DNA, pX-responsive elements include the NF-kappa B, AP-1, and CRE (cAMP response element) sites. Direct protein-protein interactions occur between viral pX and the CRE-binding transcription factors CREB and ATF. Here we examine the mechanism of the protein-protein interactions occurring between CREB and pX by using recombinant proteins and in vitro DNA-binding assays. We demonstrate that pX interacts with the basic region-leucine zipper domain of CREB but not with the DNA-binding domain of the yeast transactivator protein Gal4. The interaction between CREB and pX increases the affinity of CREB for the CRE site by an order of magnitude, although pX does not alter the rate of CREB dimerization. Methylation interference footprinting reveals differences between the CREB DNA and CREB-pX DNA complexes. These experiments demonstrate that pX titers the way CREB interacts with the CRE DNA and suggest that the basic, DNA-binding region of CREB is the target of pX. Transfection assays in PC12 cells with the CREB-dependent somatostatin promoter demonstrate a nearly 15-fold transcriptional induction after forskolin stimulation in the presence of pX. These results support the significance of the CREB-pX protein-protein interactions in vivo.
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PMID:The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. 773 90

The molecular characterization of GHRH and the GHRH receptor provides a framework for understanding the hypothalamic regulation of pituitary somatotroph function. The signaling events discerned from our investigation of GHRH receptor structure and function form the basis of a model for GHRH action, which is shown in Fig. 20. GHRH interaction with its seven transmembrane domain Gs-coupled receptor on the somatotroph (step 1) leads to the release of growth hormone from secretory granules (step 2), which is likely to involve a G protein-mediated interaction with ion channels, and to a stimulation of intracellular cAMP accumulation (step 3) (Mayo, 1992; Lin et al., 1992; Gaylinn et al., 1993). In several cell types tested, elevated cAMP leads to the phosphorylation and activation of the transcription factor CREB by protein kinase A (Gonzalez and Montminy, 1989; Sheng et al., 1991), and one target gene for CREB action is the pituitary-specific transcription factor Pit-1 or GHF-1 (step 4) (Bodner et al., 1988; Ingraham et al., 1988; McCormick et al., 1990). Pit-1 is a prototypic POU domain protein that is required for the appropriate regulation of the growth hormone gene in somatotroph cells, thus providing a pathway by which a GHRH signal can lead to increased growth hormone synthesis in the pituitary (step 5). In addition, Pit-1 is likely to directly regulate the synthesis of the GHRH receptor (step 6), in that the receptor is not expressed in the pituitary of dw/dw mice that lack functional Pit-1 (Lin et al., 1992), and a cotransfected Pit-1 expression construct can activate the GHRH receptor promoter in transiently transfected CV1 cells (Lin et al., 1993). It remains to be determined whether additional direct regulation of the GHRH receptor gene in response to the cAMP signaling pathway occurs (step 7). The inhibitory peptide somatostatin presumably interacts with this same signaling pathway through G protein-mediated suppression of the cAMP pathway (Tallent and Reisine, 1992; Bell and Reisine, 1993). In agreement with the importance of this signaling system for normal growth, a transgene encoding a nonphosphorylatable mutant CREB protein, which blocks the function of the endogenous CREB protein, is able to cause somatotroph hypoplasia and dwarfism in mice when its expression is targeted to pituitary somatotrophs (Struthers et al., 1991). Several steps in the signaling pathway leading to growth hormone secretion are subject to disruption, resulting in growth hormone deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Growth hormone-releasing hormone: synthesis and signaling. 774 Jan 67

Gene expression from the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) is mediated by three cis-acting regulatory elements known as 21-bp repeats and the transactivator protein Tax. The 21-bp repeats can be subdivided into three motifs known as A, B, and C, each of which is important for maximal gene expression in response to Tax. The B motif contains nucleotide sequences known as a cyclic AMP response element (CRE) or tax-response element which binds members of the ATF/CREB family of transcription factors. Though mutations of this element in the HTLV-I LTR eliminate tax activation, Tax will not activate most other promoters containing these CRE sites. In this study, we investigated the mechanism by which Tax activates gene expression in conjunction with members of the ATF/CREB family. We found that Tax enhanced the binding of one member of the ATF/CREB family, CREB 1, to each of the three HTLV-I LTR 21-bp repeats but not another member designated CRE-BP1 or CREB2. Tax enhanced the binding of CREB1 to nonpalindromic CRE binding sites such as those found in the HTLV-I LTR, but Tax did not enhance the binding of CREB1 to palindromic CRE binding sites such as found in the somatostatin promoter. This finding may help explain the failure of Tax to activate promoters containing consensus CRE sites. These studies were extended by use of the mammalian two-hybrid system. Tax was demonstrated to interact directly with CREB1 but not with other bZIP proteins, including CREB2 and Jun. Site-directed mutagenesis of both Tax and CREB1 demonstrated that the amino terminus of Tax and both the basic and the leucine zipper regions of CREB1 were required for direct interactions between these proteins both in vivo and in vitro. This interaction occurred in vivo and thus did not require the presence of the HTLV-I 21-bp repeats, as previously suggested. These results define the domains required for interaction between Tax and CREB that are likely critical for the activation of HTLV-I gene expression.
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PMID:Protein domains involved in both in vivo and in vitro interactions between human T-cell leukemia virus type I tax and CREB. 774 88

We have investigated the molecular basis of the variability of the somatostatin cAMP response element (CRE) function in different cell lines. All cells tested contain detectable levels of the CRE-binding protein CREB-1, which mediates transactivation in response to the cAMP-dependent protein kinase (protein kinase-A), in forms that can bind to a somatostatin CRE. Although both responsive and nonresponsive cells contain CREB-1 in heterodimers with activating transcription factor-1 (ATF-1), only cells that allow a cAMP response have a significant proportion of CREB-1 in a homodimeric form. Transfection experiments demonstrate that ATF-1 is capable of antagonizing CREB-1-dependent activation, suggesting that the ability of CREB-1 to mediate a cAMP response is down-regulated by heterodimer formation with ATF-1.
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PMID:Activating transcription factor-1 is a specific antagonist of the cyclic adenosine 3'.5'-monophosphate (cAMP) response element-binding protein-1-mediated response to cAMP. 777 75

Thyrotropin (TSH) increases 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene transcription in FRTL-5 rat thyroid cells, and the effect of TSH can be mimicked by cAMP. Sequence analysis of the rat reductase promoter has revealed a hitherto unnoticed cAMP-responsive element (CRE)-like octamer. This octamer is located between 53 and 60 nucleotides downstream of the sterol regulatory element 1; its first 6 nucleotides are identical to the consensus somatostatin CRE, and the entire octamer is identical to the fos CRE. A synthetic oligonucleotide containing the HMG-CoA reductase CRE-like octamer (RED CRE) formed protein-DNA complexes with nuclear extracts from FRTL-5 cells, which could be prevented by unlabeled CRE-containing oligonucleotides whose flanking sequences were otherwise nonidentical. The complexes were specifically supershifted by anti-CREB antibodies. FRTL-5 cells transfected with a fusion plasmid carrying the bacterial chloramphenicol acetyl transferase (CAT) under the control of the HMG-CoA reductase promoter displayed CAT activity, which was specifically stimulated by TSH. In contrast, CAT activity in FRTL-5 cells transfected with similar constructs carrying mutations in the reductase CRE was significantly lower and did not increase after TSH challenge. We suggest that the HMG-CoA reductase gene contains a functional CRE, important for TSH regulation of transcription. The data presented provide the molecular basis for a novel regulatory mechanism for HMG-CoA reductase gene expression in rat thyroid cells, which involves the direct effect of cAMP.
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PMID:Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in FRTL-5 cells. I. Identification and characterization of a cyclic AMP-responsive element in the rat reductase promoter. 779 7

Transcription factor CREB regulates cyclic AMP (cAMP)-dependent gene expression by binding to and activating transcription from cAMP response elements (CREs) in the promoters of target genes. The transcriptional transactivation functions of CREB are activated by its phosphorylation by cAMP-dependent protein kinase A (PKA). In studies of many different phenotypically distinct cells, the CRE of the somatostatin gene promoter is a prototype of a highly cAMP-responsive element regulated by CREB. We now report on a somatostatin-producing rat insulinoma cell line, RIN-1027-B2, in which transcription from the somatostatin gene promoter is paradoxically repressed by CREB. We find that CREB fails to transactivate a CRE-containing somatostatin-chloramphenicol acetyltransferase reporter even when coexpressed with the catalytic subunit of PKA. CAAT box/enhancer-binding protein beta (C/EBP beta) and C/EBP-related activating transcription factor bind to the CRE in the promoter of the somatostatin gene and transactivate transcription. CREB binds competitively with C/EBP beta to the somatostatin CRE in vitro and represses C/EBP beta-induced transcription of the CRE-containing somatostatin-chloramphenicol acetyltransferase reporter. The lack of CREB-mediated transcriptional stimulation is due to the presence of a heat-stable inhibitor of PKA that prevents activation of PKA and subsequent CREB phosphorylation in the nucleus. These findings indicate that dephosphorylated CREB is a negative regulator of C/EBP-activated transcription of the somatostatin gene promoter in RIN-1027-B2 cells.
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PMID:Impaired cyclic AMP-dependent phosphorylation renders CREB a repressor of C/EBP-induced transcription of the somatostatin gene in an insulinoma cell line. 779 50

Two cis-acting promoter elements (-108 to -100 and -49 to -33) of the mouse alpha A-crystallin gene, which is highly expressed in the ocular lens, were studied. Here we show that DE1 (-108 to -100; 5'TGACGGTG3'), which resembles the consensus cyclic AMP (cAMP)-responsive element sequence (CRE; 5'TGACGT[A/C][A/G]3'), behaves like a functional CRE site. Transfection experiments and electrophoretic mobility shift assays (EMSAs) using site-specific mutations correlated a loss of function with deviations from the CRE consensus sequence. Results of EMSAs in the presence of antisera against CREB, delta CREB, and CREM were consistent with the binding of CREB-like proteins to the DE1 sequence. Stimulation of alpha A-crystallin promoter activity via 8-bromo-cAMP, forskolin, or human T-cell leukemia virus type I Tax1 in transfections and reduction of activity of this site in cell-free transcription tests by competition with the somatostatin CRE supported the idea that DE1 is a functional CRE. Finally, Pax-6, a member of the paired-box family of transcription factors, activated the mouse alpha A-crystallin promoter in cotransfected COP-8 fibroblasts and bound to the -59 to -29 promoter sequence in EMSAs. These data provide evidence for a synergistic role of Pax-6 and CREB-like proteins for high expression of the mouse alpha A-crystallin gene in the lens.
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PMID:Transcriptional regulation of the mouse alpha A-crystallin gene: activation dependent on a cyclic AMP-responsive element (DE1/CRE) and a Pax-6-binding site. 782 34

We have previously shown that a Long Terminal Repeat (LTR) of the Intracisternal A-type Particle (IAP) element was activated by ras oncogenes. Here we show that, like the somatostatin CRE (som CRE) and the collagenase TPA Response Element (coll TRE), the IAP CRE is activated by c-jun and that Val 12 Ha-ras cooperates with c-jun to activate these motifs. Neither jun-B nor jun-D activated the IAP CRE, although they were able to act on the som CRE and the coll TRE and to synergize with ras. The CREB factor activated both CREs and modestly inhibited the coll TRE, but diminished the effect of ras on the coll TRE. Finally, forskolin was shown to cooperate with Ha-ras to activate the CRE and the coll TRE. Taken together, these results show that CREB is not involved in ras activation of the CRE and suggest that c-jun is at least one of the elements implicated in this phenomenon.
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PMID:Differential effects of c-jun and CREB on c-AMP response element activation by Ha-ras. 790 82

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