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

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

Somatostatin receptor (sst) subtype 2 mRNA is potently regulated by 17beta-estradiol (E2) in a time and dose-dependent manner in the estrogen receptor (+) human breast cancer cell line T47D. To explore the mechanism involved in E2 regulated expression of sst2, we isolated and characterized a genomic clone containing over 5.3 kilobase pairs (kb) of the 5' flanking region of the human sst2 gene. The 5'-flanking region lacks both TATA and CCAAT boxes. Primer extension and RNAase protection analysis revealed the existence of two transcriptional start sites, located within an initiator-like sequence, 85 and 82 bp upstream of the translational initiation methionine. The 5.3-kb 5'-flanking region was an active promoter in T47D cells but was inactive in MDA MB 435s cells, a human breast cancer cell line that does not express sst2. Deletion analysis identified both positive and negative regulatory elements within the 5.3-kb fragment. Furthermore, transcriptional regulation by E2 was mediated by a distal 1.5-kb fragment located 3.8 kb from the transcriptional start sites. Determining the precise ERE will provide important insights into the complex regulation of sst2 expression in normal and neoplastic tissue.
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PMID:Characterization of the promoter region of the human somatostatin receptor subtype 2 gene and localization of sequences required for estrogen-responsiveness. 970 75

Somatostatin exerts inhibitory effects on virtually all endocrine and exocrine secretions. The somatostatin receptor subtype 2 (sst2) acts as a critical molecule for growth hormone regulation and cell proliferation. We investigated the structure and regulation of the human sst2 gene. A genomic clone including the sst2 gene was isolated, 1.5 kb of the promoter was sequenced and putative transcription factor binding sites were identified. The transcription start site was located 93 nucleotides upstream of the translation start site. The nucleotide sequences of the complete gene and 0.5 kb of 3' region were determined. A possible polyadenylation signal was identified. Transcriptional regulation was investigated by transient transfections using various promoter fragments. A -1100 sst2 promoter directed significant levels of luciferase expression in GH4 rat pituitary cells and Skut1-B endometrium cells whereas only low activity was detected in JEG3 chorion carcinoma cells or COS-7 monkey kidney cells. A minimal -252 promoter allowed cell specific expression. We did not find any regulation of the sst2 promoter by somatostatin, forskolin, TRH, TPA, T3, and 17beta-estradiol. Glucocorticoids lead to a significant inhibition of sst2 promoter activity. Further mapping suggest a glucocorticoid-responsive element between -905 and -707 and between -252 and -163. These studies demonstrate the nature of the human sst2 gene and identify its 5' and 3' flanking regions. Furthermore, specific activity of the promoter and regulation by various hormones is demonstrated.
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PMID:Genomic structure and transcriptional regulation of the human somatostatin receptor type 2. 1061 99

We screened the Berkeley "Drosophila Genome Project" database with "electronic probes" corresponding to conserved amino acid sequences from the five known rat somatostatin receptors. This yielded alignment with a Drosophila genomic clone that contained a DNA sequence coding for a protein, having amino acid sequence identities with the rat galanin receptors. Using PCR with Drosophila cDNA as a template, and oligonucleotide probes coding for the exons of the presumed Drosophila gene, we were able to clone the cDNA for this receptor. The Drosophila receptor has most amino acid sequence identity with the three mammalian galanin receptors (37% identity with the rat galanin receptor type-1, 32% identity with type-2, and 29% identity with type-3). Less sequence identity exists with the mammalian opioid/nociceptin-orphanin FQ receptors (26% identity with the rat micro opioid receptor), and mammalian somatostatin receptors (25% identity with the rat somatostatin receptor type-2). The novel Drosophila receptor gene contains ten introns and eleven exons and is located at the distal end of the X chromosome.
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PMID:Molecular cloning and genomic organization of a novel receptor from Drosophila melanogaster structurally related to mammalian galanin receptors. 1069 83

Synthetic GH secretagogues stimulate GH release through binding to a recently cloned specific GH secretagogue receptor (GHS-R). The endogenous ligand of this receptor may be part of a new endocrine pathway controlling GH secretion. Two different receptor variants, type 1a and 1b, have been described that differ in their 3'-terminal amino acids. We investigated the genomic structure and transcriptional regulation of the human GHS-R. An 18-kb genomic clone including sequences encoding for the two GHS-R variants was isolated. Sequencing revealed that the two variants originate from specific RNA processing of a single gene that spans approximately 4.1 kb. The transcription start site was defined by 5'-inverse PCR analysis at position -227. RT-PCR analysis points to differential transcriptional initiation and processing. Type 1a is encoded by two exons; 2152 bp of intronic sequence are removed by splicing at position 796/797 relative to the translation start site. Type 1b is encoded by a single exon. A putative polyadenylation signal consensus motif was identified at position +4118; 2.7 kb of the 5'-flanking region were sequenced, and putative transcription factor binding sites were identified. Transcriptional regulation was investigated by transient transfections using promoter fragments ranging in size from 168-1745 bp; 1745 bp of the GHS-R promoter directed significant levels of luciferase expression in GH(4) rat pituitary cells, whereas no activity was detected in monkey kidney COS-7 cells, human endometrium Skut-1B cells, mouse hypothalamic LHRH neuronal GT1-7 cells, or mouse corticotroph pituitary AtT20 cells. A minimal 309-bp promoter allowed pituitary-specific expression. Its activity in COS-7 cells was enhanced by cotransfection of the pituitary-specific transcription factor Pit-1. We did not find any regulation of the GHS-R promoter by forskolin, somatostatin, insulin-like growth factor I, or 12-O-tetraphorbol 12-myristate 13-acetate. Thyroid hormone and estrogen lead to a significant stimulation; glucocorticoids lead to a significant inhibition. Further mapping suggests a thyroid hormone-responsive element, an estrogen-responsive element, and a glucocorticoid-responsive element located between -309 and the translation start codon. These studies demonstrate the nature of the human GHS-R gene and identify its 5'-flanking region. Furthermore, pituitary-specific activity of the promoter and regulation by various hormones are demonstrated.
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PMID:Genomic structure and transcriptional regulation of the human growth hormone secretagogue receptor. 1135 16

Somatostatin (SRIF) exerts inhibitory effects on virtually all endocrine and exocrine secretions. Five distinct SRIF receptor subtypes (sst 1-5) have been identified. In contrast to the other subtypes, very little is known about specific functions of sst4. We investigated structure and regulation of the human sst4 gene. A genomic clone containing the 5' region of the sst4 gene was isolated. 1.5 kb of the promoter was sequenced and putative transcription factor binding sites were identified. The transcription start site was located 88 nucleotides upstream of the translation start site. A -984 sst4 promoter directed significant levels of luciferase expression in GH4 rat pituitary cells, Skut-1B endometrium cells, and BEAS-2B human bronchial epithelial cells, whereas only low activity was detected in JEG3 chorion carcinoma cells or COS-7 monkey kidney cells. A minimal -209 promoter allowed cell specific expression, its activity in COS-7 cells is not enhanced by co-transfection of the pituitary-specific transcription factor Pit-1. An enhancer element was localized between nt -459 and -984. We did not find any regulation of the sst4 promoter region analyzed by SRIF, forskolin, TPA, IGF-1, EGF, T3, glucocorticoids or 17beta-estradiol. These studies identify the 5' region of the sst4 gene. Furthermore, specific activity of the promoter in various cell lines is demonstrated.
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PMID:Characterization of the human somatostatin receptor type 4 promoter. 1191 48