Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transactivation of genes through the cAMP-regulated enhancer (CRE) is proposed to occur by the binding and phosphorylation of the transcription factor CREB (CRE-binding protein). Originally believed to be a single protein, more than 10 different CREB proteins have been cloned. The contributions of each of these factors to gene regulation have yet to be determined unambiguously. We have isolated a CREB cDNA that contains a mutation of a single amino acid in the DNA-binding domain. In gel shift assays, this mutant, designated KCREB, is unable to bind to the somatostatin (SS) CRE. In addition, KCREB acts as a dominant repressor of the wild-type factor, blocking the ability of wild-type CREB to bind to the CRE when present as a KCREB:CREB heterodimer. The KCREB mutant also acts as a dominant repressor in vivo, completely blocking the ability of wild-type CREB to mediate induction by protein kinase-A of a SS CRE reporter gene in F9 teratocarcinoma cells. We have used this mutant to analyze the participation of CREB in the induction of the SS promoter in CA-77 cells, a medullary thyroid carcinoma cell line that produces high levels of SS. Although KCREB can block a portion of the cAMP induction of the SS promoter in CA-77 cells, approximately 45% of the induction remains insensitive to the mutant. These data support the paradigm that CREB is involved in the cAMP induction of SS in vivo. Furthermore, the inability of KCREB to completely block cAMP-mediated SS expression in CA-77 cells suggests that additional factors may contribute to the cAMP regulation of CRE function.
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PMID:A dominant repressor of cyclic adenosine 3',5'-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. 135 57

The estradiol-binding protein (EBP) in extracts of rat and rabbit pancreata was characterized by sucrose density gradient analysis, immunoaffinity adsorption and Western blot (immunoblot) analysis using polyclonal antibodies raised against EBP. Rat pancreatic extracts labeled with 3H-estradiol contained a readily resolvable peak of steroid-binding activity that sedimented as a 4S complex on sucrose density gradients in the presence or absence of 0.4 M KCl. Estrogen receptor (ER) from calf uterine cytosols sedimented as a 4S complex on gradients containing 0.4 M KCl and as an 8S entity on gradients without KCl. Incubation of cytosol fractions from rat pancreas and calf uterus with benzoyl-DL-arginyl-p-nitroanilide (BAN) increased specific binding of 3H-estradiol to EBP but not to ER. Furthermore, two distinct site-specific antibodies to the DNA-binding domain of ER caused a marked increase in sedimentation rate of 3H-estradiol-labeled ER while normal rabbit serum and antibodies against EBP were ineffective in this regard. These data suggest that a significant portion, if not all, of the DNA-binding domain of ER is absent from EBP. Examination of the amino acid sequence of the DNA-binding domain of ER revealed a region of 10 amino acids that is significantly homologous to somatostatin, a tetradecapeptide that is a co-ligand in the binding of 3H-estradiol to EBP. Based on this observation, a possible mode of action of EBP in pancreatic acinar cells is proposed.
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PMID:Site-specific antibodies to the DNA-binding domain of estrogen receptor distinguish this protein from the 3H-estradiol-binding protein in pancreas. 138 3

In this report, we describe the isolation and initial characterization of a Drosophila protein, dCREB-A, that can bind the somatostatin cyclic AMP (cAMP)-responsive element and is capable of activating transcription in cell culture. Sequence analysis demonstrates that this protein is a member of the leucine zipper family of transcription factors. dCREB-A is unusual in that it contains six hydrophobic residue iterations in the zipper domain rather than the four or five commonly found in this group of proteins. The DNA-binding domain is more closely related to mammalian CREB than to the AP-1 factors in both sequence homology and specificity of cAMP-responsive element binding. In embryos, dCREB-A is expressed in the developing salivary gland. A more complex pattern of expression is detected in the adult; transcripts are found in the brain and optic lobe cell bodies, salivary gland, and midgut epithelial cells of the cardia. In females, dCREB-A is expressed in the ovarian columnar follicle cells, and in males, dCREB-A RNA is seen in the seminal vesicle, ejaculatory duct, and ejaculatory bulb. These results suggest that the dCREB-A transcription factor may be involved in fertility and neurological functions.
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PMID:A cyclic AMP-responsive element-binding transcriptional activator in Drosophila melanogaster, dCREB-A, is a member of the leucine zipper family. 150 8

Phenotypically distinct islet tumor cell lines may recapitulate certain of the developmental pathways of normal islet cell differentiation by expressing a combinatorial set of positively and negatively acting DNA-binding proteins to allow for the programmed expression of genes encoding polypeptide hormones. The structure of one of these DNA-binding proteins, a cyclic AMP-responsive protein (CREB) that binds specific DNA regulatory elements in the somatostatin gene, has been deduced from the sequence of a cloned cDNA. The CREB protein contains a DNA-binding domain separate from a cAMP-dependent protein kinase A activation domain. Further characterizations of the genes encoding the DNA-binding proteins should help to elucidate the cellular processes involved in islet cell differentiation and the genesis of tumors.
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PMID:Factors that determine cell-specific gene expression in pancreatic endocrine tumor cells. 255 19

Insulin increases expression of somatostatin-chloramphenicol acetyltransferase (CAT) constructs 10-fold and thymidine kinase-CAT constructs 5-fold in GH4 cells. These responses are similar to our previously reported data on insulin-increased prolactin-CAT expression. They are also observed in HeLa cells and are thus not cell type specific. The evidence suggests that the insulin responsiveness of these genes is mediated by an Ets-related transcription factor. First, linker-scanning mutations and/or deletions of the prolactin, somatostatin, and thymidine kinase promoters suggest that their insulin responsiveness is mediated by the sequence CGGA. This sequence is identical with the response element of the Ets-related transcription factors. Second, CGGA-containing sequences placed at -88 in the delta MTV-CAT reporter plasmid conferred insulin responsiveness to the mammary tumor virus promoter. Third, expression of the DNA-binding domain of c-Ets-2, which acts by blocking effects mediated by Ets-related transcription factors, inhibits the response of these promoters to insulin. Finally, the Ets-related proteins Sap and Elk-1 bind to the prolactin, somatostatin, and thymidine kinase insulin-response elements. An Ets-like element was found in all insulin-sensitive promoters examined and may serve a similar function in those promoters.
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PMID:A consensus insulin response element is activated by an Ets-related transcription factor. 749 46

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

Pancreas formation is prevented in mice carrying a null mutation in the PDX-1 homeoprotein, demonstrating a key role for this factor in development. PDX-1 can also bind to and activate transcription from cis-acting regulatory sequences in the insulin and somatostatin genes, which are expressed in pancreatic islet beta and delta cells, respectively. In this study, we compared the functional properties of PDX-1 with those of the closely related Xenopus homeoprotein XIHbox8. Analysis of chimeras between PDX-1, XIHbox8, and the DNA-binding domain of the Saccharomyces cerevisiae transcription factor GAL4 revealed that their transactivation domain was contained within the N-terminal region (amino acids 1 to 79). Detailed mutagenesis of this region indicated that transactivation is mediated by three highly conserved sequences, spanning amino acids 13 to 22 (subdomain A), 32 to 38 (subdomain B), and 60 to 73 (subdomain C). These sequences were also required by PDX-1 to synergistically activate insulin enhancer-mediated transcription with another key insulin gene activator, the E2A-encoded basic helix-loop-helix E2-5 and E47 proteins. These results indicated that N-terminal sequences conserved between the mammalian PDX-1 and Xenopus XIHbox8 proteins are important in transcriptional activation. Stable expression of the PDX-1 deltaABC mutant in the insulin- and PDX-1-expressing betaTC3 cell line resulted in a threefold reduction in the rate of endogenous insulin gene transcription. Strikingly, the level of the endogenous PDX-1 protein was reduced to very low levels in these cells. These results suggest that PDX-1 is not absolutely essential for insulin gene expression in betaTC3 cells. We discuss the possible significance of these findings for insulin gene transcription in islet beta cells.
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PMID:Functional characterization of the transactivation properties of the PDX-1 homeodomain protein. 919 33

B-myb, a member of the myb gene family, was originally isolated based on its high homology with c-myb in the DNA-binding domain. Previously we showed that B-myb is expressed in bovine vascular smooth muscle cells (SMCs) in a cell cycle-dependent fashion, and inhibits type I collagen gene promoter activity. Here, we have explored its role in regulation of another fibrillar collagen gene, Col5A2, encoding the (alpha2 chain of type V collagen. Ectopic expression of B-Myb decreased alpha 2(V) promoter activity and endogenous alpha 2(V) collagen mRNA levels. The responsive region of the alpha 2(V) collagen gene was localized to a fragment including 100 bp of basal promoter and 150 bp of exon 1 sequences, which contained two CRE-like elements. Binding to these elements increased upon deprivation of serum-growth factors, when expression of the Col5A2 gene is elevated, leading us to test their role despite the failure of excess unlabelled CRE oligonucleotide from the somatostatin gene to successfully compete for binding. Mutation of the elements significantly decreased the basal level of alpha2(V) collagen promoter activity and ablated inhibition by B-Myb. Furthermore, addition of B-Myb-glutathionine S-transferase fusion protein inhibited complex formation. Thus, these results confirm a major role for B-Myb in mediating intracellular signals controlling collagen gene expression in vascular SMCs. A model of indirect repression of the Col5A2 gene by B-Myb, via interaction with a positively-acting matrix regulatory factor, termed MRF-V, is discussed.
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PMID:B-Myb represses trans-activation of the Col5A2 collagen promoter indirectly via inhibition of binding of factors interacting with positive elements within the first exon. 1042 46

To investigate the molecular mechanism(s) of action of catecholamines on the expression of the angiotensinogen (ANG) gene in kidney proximal tubular cells, we used opossum kidney (OK) cells with a fusion gene containing the 5'-flanking regulatory sequence of the rat ANG gene fused with a human growth hormone (hGH) gene as a reporter, pOGH (rANG N-1498/+18), permanently integrated into their genomes. The level of expression of the ANG-GH fusion gene was quantified by the amount of immunoreactive-hGH (IR-hGH) secreted into the medium. The addition of norepinephrine (NE), isoproterenol (a beta1/beta2-adrenergic receptor (AR) agonist) and iodoclonidine (an alpha2-AR agonist) stimulated the expression of the ANG-GH fusion gene in a dose-dependent manner, whereas the addition of epinephrine and phenylephrine (alpha1-AR agonist) had no effect. The stimulatory effect of NE was blocked by the presence of propranolol (beta-AR blocker), atenolol (beta1-AR blocker), yohimbine (alpha2-AR blocker), Rp-cAMP (an inhibitor of cAMP-dependent protein kinase AI & AII) and staurosporine (an inhibitor of protein kinase C), but was not blocked by ICI 118, 551 (beta2-AR blocker) and prazosin (alpha1-AR blocker). The addition of a combination of isoproterenol and iodoclonidine or a combination of 8-Bromo-cAMP (8-Br-cAMP) and phorbol 12-myristate (PMA) synergistically stimulated the expression of the ANG-GH fusion gene as compared to the addition of isoproterenol, iodoclonidine, 8-Br-cAMP or PMA alone. Furthermore, the addition of NE, 8-Br-cAMP or PMA stimulated the expression of pOGH (rANG N-806/-779/-53/+18), a fusion gene containing the putative cAMP responsive element (CRE, ANG N-806/-779) upstream of the ANG promoter (ANG N-53/+18) in OK cells, but had no effect on the expression of fusion genes containing the mutant of the CRE. Gel mobility shift assays revealed that the ANG-CRE binds with the DNA-binding domain (bZIP254-327) of the cAMP-responsive binding protein (CREB). The binding of the labeled ANG-CRE to CREB (bZIP254-327) was displaced by unlabeled ANG-CRE and the CRE of the somatostatin gene but not by the mutants of the ANG-CRE. Finally, NE stimulated the phosphorylation of CREB in OK cells. These studies demonstrate that the molecular mechanism(s) of NE action on the expression of the ANG gene in OK cells may be mediated via both the PKA and PKC signalling pathways and via the phosphorylation of CREB. The phosphorylated CREB then interacts with the CRE in the 5'-flanking region of the ANG gene and subsequently stimulates the gene expression.
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PMID:Catecholamines and angiotensinogen gene expression in kidney proximal tubular cells. 1110 38