Characterization and Transcriptional Regulation of the Human Somatostatin Receptor Subtype 1 Gene

Abstract

Somatostatin (SRIF) exerts inhibitory effects on virtually all endocrine and exocrine secretions. At least five distinct human SRIF receptors have been identified (sst1-sst5). Analysis of the promoter region may provide tools to understand transcriptional regulation of ssts in various tissues, indicating specific functions. Transcriptional regulation of the human sst1 was analyzed in the present study. Total RNA from a human somatotropic pituitary tumor was reverse transcribed. 5′cDNA regions of the human sst1 were cloned using an adapted inverse PCR method. Among the 15 PCR clones analyzed, 9 demonstrated an extended 5′-utr of 266 nucleotides, determining a thymidine residue as a major transcription start site. No introns were evident in the 5′-utr region. The promoter region lacked consensus sites for TATA or CAAT boxes, YY1, or an initiator sequence, but contained two CpG islands. Different lengths of 5′-flanking regions cloned by PCR were placed upstream of the luciferase reporter gene and transiently transfected into various cell lines. The 2834 nt of the promoter region directed significant transcriptional activity in a somatotropic pituitary cell line, but neither in COS-7 monkey kidney cells nor in AtT-20 murine corticotrope cells. Transcriptional activity was not affected by incubation with various hormones. Several putative transcription factor binding sites inducing the cell-type specific activity were identified.

Key words

somatostatin receptor - G-protein coupled receptor - structure - regulation

References

• 1 Badway AC, Blake AD. Somatostatin: a hormone for the heart?.  Curr Vasc Pharmacol. 2005;  3 125-131
• 2 Hofland LJ, Lamberts SW. Somatostatin receptors in pituitary function, diagnosis and therapy.  Front Horm Res. 2004;  32 235-252
• 3 Reichlin S. Somatostatin.  N Engl J Med. 1983;  309 1495-1501
• 4 Reubi JC, Laissue JA. Multiple actions of somatostatin in neoplastic disease.  Trends Pharmacol Sci. 1995;  16 110-115
• 5 Ballian N, Brunicardi FC, Wang XP. Somatostatin and its receptors in the development of the endocrine pancreas.  Pancreas. 2006;  33 1-12
• 6 Gillies G. Somatostatin: the neuroendocrine story.  Trends Pharmacol Sci. 1997;  18 87-95
• 7 Meyerhof W. The elucidation of somatostatin receptor functions: a current view.  Rev Physiol Biochem Pharmacol. 1998;  133 55-108
• 8 Reisine T, Bell GI. Molecular biology of somatostatin receptors.  Endocr Rev. 1995;  16 427-442
• 9 Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.  Eur J Endocrinol. 2002;  146 707-716
• 10 Thermos K, Bagnoli P, Epelbaum J, Hoyer D. The somatostatin sst1 receptor: an autoreceptor for somatostatin in brain and retina?.  Pharmacol Ther. 2006;  110 455-464
• 11 Lahlou H, Guillermet J, Hortala M. et al . Molecular signaling of somatostatin receptors.  Ann N Y Acad Sci. 2004;  1014 121-131
• 12 Sharma K, Patel YC, Srikant CB. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3.  Mol Endocrinol. 1996;  10 1688-1696
• 13 Helyes Z, Pinter E, Nemeth J. et al . Effects of the somatostatin receptor subtype 4 selective agonist J-2156 on sensory neuropeptide release and inflammatory reactions in rodents.  Br J Pharmacol. 2006;  149 405-415
• 14 Dal Monte M, Petrucci C, Vasilaki A. et al . Genetic deletion of somatostatin receptor 1 alters somatostatinergic transmission in the mouse retina.  Neuropharmacology. 2003;  45 1080-1092
• 15 Cammalleri M, Cervia D, Langenegger D. et al . Somatostatin receptors differentially affect spontaneous epileptiform activity in mouse hippocampal slices.  Eur J Neurosci. 2004;  20 2711-2721
• 16 Shen LP, Pictet RL, Rutter WJ. Human somatostatin I: sequence of the cDNA.  Proc Natl Acad Sci USA. 1982;  79 4575-4579
• 17 Hauser F, Meyerhof W, Wulfsen I, Schonrock C, Richter D. Sequence analysis of the promoter region of the rat somatostatin receptor subtype 1 gene.  FEBS Lett. 1994;  345 225-228
• 18 Debus N, Dutour A, Vuaroqueaux V, Oliver C, Ouafik L. The ovine somatostatin receptor subtype 1 (osst1): partial cloning and tissue distribution.  Domest Anim Endocrinol. 2001;  21 73-84
• 19 Lin X, Janovick JA, Brothers S, Conn PM, Peter RE. Molecular cloning and expression of two type one somatostatin receptors in goldfish brain.  Endocrinology. 1999;  140 5211-5219
• 20 Zeiner M, Gehring U. Cloning of 5′ cDNA regions by inverse PCR.  Biotechniques. 1994;  17 1050-1054
• 21 Solovyev V, Salamov A. The Gene-Finder computer tools for analysis of human and model organisms genome sequences.  Proc Int Conf Intell Syst Mol Biol. 1997;  5 294-302
• 22 Heinemeyer T, Wingender E, Reuter I. et al . Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL.  Nucleic Acids Res. 1998;  26 362-367
• 23 Milanesi L, D’Angelo D, Rogozin IB. GeneBuilder: interactive in silico prediction of gene structure.  Bioinformatics. 1999;  15 612-621
• 24 Panetta R, Greenwood MT, Warszynska A. et al . Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28.  Mol Pharmacol. 1994;  45 417-427
• 25 Thoss VS, Perez J, Probst A, Hoyer D. Expression of five somatostatin receptor mRNAs in the human brain and pituitary.  Naunyn Schmiedebergs Arch Pharmacol. 1996;  354 411-419
• 26 Kumar U, Sasi R, Suresh S. et al . Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis.  Diabetes. 1999;  48 77-85
• 27 Patel YC. Somatostatin and its receptor family.  Front Neuroendocrinol. 1999;  20 157-198
• 28 Smith WH, Nair RU, Adamson D. et al . Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts.  J Endocrinol. 2005;  187 379-386
• 29 Petersenn S, Rasch AC, Bohnke C, Schulte HM. Identification of an upstream pituitary-active promoter of human somatostatin receptor subtype 5.  Endocrinology. 2002;  143 2626-2634
• 30 Glos M, Kreienkamp HJ, Hausmann H, Richter D. Characterization of the 5′-flanking promoter region of the rat somatostatin receptor subtype 3 gene.  FEBS Lett. 1998;  440 33-37
• 31 Gordon DF, Woodmansee WW, Lewis SR. et al . Cloning of the mouse somatostatin receptor subtype 5 gene: promoter structure and function.  Endocrinology. 1999;  140 5598-5608
• 32 Woodmansee WW, Mouser RL, Gordon DF. et al . Mutational analysis of the mouse somatostatin receptor type 5 gene promoter.  Endocrinology. 2002;  143 2268-2276
• 33 Petersenn S, Rasch AC, Presch S, Beil FU, Schulte HM. Characterization of the human somatostatin receptor type 4 promoter.  Mol Cell Endocrinol. 2002;  188 75-83
• 34 Kraus J, Woltje M, Schonwetter N, Hollt V. Gene structure and regulation of the somatostatin receptor type 2.  J Physiol Paris. 2000;  94 199-204
• 35 Petersenn S, Rasch AC, Presch S, Beil FU, Schulte HM. Genomic structure and transcriptional regulation of the human somatostatin receptor type 2.  Mol Cell Endocrinol. 1999;  157 75-85
• 36 Schafer J, Baumeister H, Lorenz A, Meyerhof W. Localization of somatostatin receptor subtype mRNA in the rat gastrointestinal tract and regulation of SSTR1 gene expression.  Z Ernahrungswiss. 1998;  37 ((Suppl 1)) 75-79
• 37 Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes.  J Mol Biol. 1987;  196 261-282
• 38 Cervia D, Nunn C, Fehlmann D. et al . Pharmacological characterisation of native somatostatin receptors in AtT-20 mouse tumour corticotrophs.  Br J Pharmacol. 2003;  139 109-121
• 39 Patel YC, Panetta R, Escher E, Greenwood M, Srikant CB. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype.  J Biol Chem. 1994;  269 1506-1509
• 40 Faisst S, Meyer S. Compilation of vertebrate-encoded transcription factors.  Nucleic Acids Res. 1992;  20 3-26
• 41 de la Hoya M, Vila V, Jimenez O, Castrillo JL. Anterior pituitary development and Pit-1/GHF-1 transcription factor.  Cell Mol Life Sci. 1998;  54 1059-1066
• 42 Baumeister H, Wegner M, Richter D, Meyerhof W. Dual regulation of somatostatin receptor subtype 1 gene expression by pit-1 in anterior pituitary GH3 cells.  Mol Endocrinol. 2000;  14 255-271
• 43 Sipos L, Gyurkovics H. Long-distance interactions between enhancers and promoters.  FEBS J. 2005;  272 3253-3259
• 44 Moore DD, Marks AR, Buckley DI. et al . The first intron of the human growth hormone gene contains a binding site for glucocorticoid receptor.  Proc Natl Acad Sci USA. 1985;  82 699-702
• 45 Bruno JF, Xu Y, Berelowitz M. Somatostatin regulates somatostatin receptor subtype mRNA expression in GH3 cells.  Biochem Biophys Res Commun. 1994;  202 1738-1743
• 46 Park S, Kamegai J, Johnson TA, Frohman LA, Kineman RD. Modulation of pituitary somatostatin receptor subtype (sst1-5) messenger ribonucleic acid levels by changes in the growth hormone axis.  Endocrinology. 2000;  141 3556-3563
• 47 Xu Y, Berelowitz M, Bruno JF. Dexamethasone regulates somatostatin receptor subtype messenger ribonucleic acid expression in rat pituitary GH4C1 cells.  Endocrinology. 1995;  136 5070-5075
• 48 James RA, Sarapura VD, Bruns C. et al . Thyroid hormone-induced expression of specific somatostatin receptor subtypes correlates with involution of the TtT-97 murine thyrotrope tumor.  Endocrinology. 1997;  138 719-724
• 49 Djordjijevic D, Zhang J, Priam M. et al . Effect of 17beta-estradiol on somatostatin receptor expression and inhibitory effects on growth hormone and prolactin release in rat pituitary cell cultures.  Endocrinology. 1998;  139 2272-2277

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