HGNC Approved Gene Symbol: SSTR2
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:73,165,010-73,176,633 (from NCBI)
Somatostatin (182450) exerts its biologic effects by binding to specific high-affinity receptors, which appear in many cases to be coupled to GTP-binding proteins.
Patel et al. (1993) showed that alternative splicing of human SSTR2 generates 2 splice variants that encode proteins with different C termini.
Patel et al. (1993) determined that the SSTR2 gene contains at least 1 intron. In contrast, other members of the somatostatin receptor family are intronless.
Greenwood et al. (1995) characterized 3.8 kb of sequence upstream of the first codon of SSTR2. The region shares features found in other G protein-coupled receptor gene promoters, including a number of GC-rich domains and the lack of coupled TATAA and CAAT motifs.
Pscherer et al. (1996) isolated the promoter region of the SSTR2 gene and identified a putative E-box binding site. Dorflinger et al. (1999) identified a TC box just 5-prime of the E box in the mouse and human SSTR2 promoters.
By analysis of segregation in a panel of reduced human-hamster somatic cell hybrids, Yamada et al. (1993) assigned the SSTR2 gene to chromosome 17. By fluorescence in situ hybridization, they regionalized the gene to 17q24. By interspecific backcross analysis, Brinkmeier and Camper (1997) mapped the Sstr2 gene to mouse chromosome 11.
Pscherer et al. (1996) cloned a transcription factor, SEF2 (602272), that bound the E-box site in the SSTR2 promoter.
Dorflinger et al. (1999) showed that rodent Mibp1 (HIVEP2; 143054) bound specifically to the TC box in the human SSTR2 promoter and could activate transcription. Mibp1 interacted with Sef2 to enhance transcription from the basal Sstr2 promoter in murine brain.
Zatelli et al. (2001) determined that the human medullary thyroid carcinoma cell line TT (characterized by the presence of a mutation involving exon 11 of RET, 164761.0012), expresses all SSTR subtypes; that SSTR2 activation inhibits DNA synthesis and cell proliferation, whereas SSTR5 (182455) activation increases DNA synthesis; and that an SSTR2 preferential agonist can antagonize SSTR5-selective agonist action, and vice versa. These findings suggest a tissue-specific function and a tissue-specific interaction between the 2 receptors.
Raggi et al. (2000) investigated if expression of SSTR2 is related to the clinical outcome of neuroblastoma. They performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of SSTR2 mRNA was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. They found that SSTR2 mRNA was variably expressed in all neuroblastoma tumors with a relevant reduction in the more advanced stage. Analysis of Kaplan-Meier curves indicated that SSTR2 expression is positively related to the overall and event-free survival. Expression of SSTR2 was negatively related to tumor stage and MYCN (164840) amplification, a poor prognostic factor. However, the prognostic information derived from SSTR2 is apparently independent from MYCN amplification, as assessed by stratifying SSTR2 values according to MYCN. The authors concluded that SSTR2 expression represents a prognostic marker for neuroblastoma. They also inferred that the main clinical value of a quantitative measure of SSTR2 lies in its ability to detect patients at low risk, independently from other prognostic factors, including MYCN amplification.
SSTR2 gene expression is lost in 90% of human pancreatic adenocarcinomas (Buscail et al., 1996). Stable SSTR2 transfection of human pancreatic cells, which do not endogenously express SSTR2, inhibits cell proliferation, tumorigenicity, and metastasis. These effects occur as a consequence of an autocrine SSTR2-dependent loop, whereby SSTR2 induces expression of its own ligand, somatostatin. Guillermet et al. (2003) investigated whether SSTR2 induces apoptosis in the same SSTR2-transfected pancreatic cells. They demonstrated that SSTR2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. They suggested that using a combined gene therapy based on the cotransfer of the SSTR2 gene and a gene for a nontoxic death ligand would be relevant to the clinical management of chemoresistant pancreatic adenocarcinoma.
In a cell line derived from a human small cell lung cancer (182280), Zhang et al. (1995) found a point mutation in codon 188 of the SSTR2 gene; TGG for tryptophan was changed to TGA for a stop codon causing loss of 182 C-terminal amino acid residues of the protein. The cell line studied, COR-L103, produces ACTH ectopically, and somatostatin does not inhibit ACTH release from the cells. Zhang et al. (1995) found that SSTR2 is not expressed in the plasma membranes of COR-L103 cells due to the point mutation, but concluded that this may have no influence on the effect of somatostatin on ACTH secretion.
Ardjomand et al. (2003) investigated the distribution of SSTR2, SSTR3 (182453), and SSTR5 in uveal melanomas (155720) and their diagnostic and possible therapeutic value. All 25 uveal melanomas studied were positive for SSTR2: SSTR2A was expressed in 15 of 25; SSTR2B in 23 of 25; SSTR3 in 7 of 25; and SSTR5 in 13 of 25. A Kaplan-Meier survival curve showed a significantly better ad vitam prognosis for patients with tumors expressing high levels of SSTR2. Because a melanoma cell proliferation assay showed an inhibitory effect of up to 36% +/- 6% using octreotide or vapreotide, somatostatin analogs might be beneficial in the treatment of patients with ocular melanomas.
Normal pancreatic beta cells express SSTRs. Bertherat et al. (2003) determined the prevalence of SSTR expression in vitro and characterized SSTR subtype binding in insulinomas and its correlation with in vivo SSTR scintigraphy. Semiquantitative RT-PCR of SSTR mRNA was performed for 20 insulinomas. SSTR2 and SSTR5 (182455) were expressed in 70%, SSTR1 (182451) in 50%, and SSTR3 and SSTR4 (182454) subtypes only in 15 to 20% of the tumors. Displacement experiments with ligands of higher affinity for each of the SSTRs revealed significant binding with the SSTR2 and SSTR5 ligands in 72%, SSTR3 in 44%, SSTR1 in 44%, and SSTR4 in 28% of cases. The authors concluded that loss of expression of SSTR2/SSTR5 in a third of insulinomas may be involved in beta-cell dysfunction.
Using an SSTR2-selective antagonist, Ren et al. (2003) showed that both SSTR2 and SSTR5 participate in the suppression of GH (139250) by somatostatin (182450) in the human fetal pituitary. The results demonstrated that either SSTR2 or STR5 may independently suppress GH secretion from the pituitary. Activation of both SSTR2 and SSTR5 induced a functional, synergistic association of the receptor subtypes that resulted in enhanced suppression of G secretion.
Filopanti et al. (2005) determined if SNPs in the SSTR2 and SSTR5 genes correlated with responsiveness to somatostatin analogs in a cohort of acromegalic patients. Three SNPs (A-83G, C-57G, and T80C) of SSTR2 and 3 (T-461C, C325T, and C1004T) of SSTR5 were analyzed in 66 acromegalic patients with different responsiveness to somatostatin analogs and 66 healthy controls. Allele frequencies in patients and controls were similar. No association between SSTR2 genotypes and GH and IGF1 (147440) levels was found. In contrast patients homozygous or heterozygous for the SSTR5 C1004 allele (P+) showed basal IGF1 levels significantly lower than patients homozygous for the T1004 allele (P-). Moreover, serum GH levels were lower in patients with P+/T- haplotype (having C1004 allele and no T-461 allele) than in those with P-/T+. No correlation between SSTR2 and SSTR5 genotypes, responsiveness to somatostatin therapy, or mRNA expression in the removed adenomas (n = 10) was found. The authors concluded that these data suggest a role for SSTR5 T-461C and C1004T alleles in influencing GH and IGF1 levels in patients with acromegaly, whereas SSTR2 and SSTR5 variants seem to have a minor role in determining the responsiveness to somatostatin analogs.
Ardjomand, N., Ardjomand, N., Schaffler, G., Radner, H., El-Shabrawi, Y. Expression of somatostatin receptors in uveal melanomas. Invest. Ophthal. Vis. Sci. 44: 980-987, 2003. [PubMed: 12601018] [Full Text: https://doi.org/10.1167/iovs.02-0481]
Bertherat, J., Tenenbaum, F., Perlemoine, K., Videau, C., Alberini, J. L., Richard, B., Dousset, B., Bertagna, X., Epelbaum, J. Somatostatin receptors 2 and 5 are the major somatostatin receptors in insulinomas: an in vivo and in vitro study. J. Clin. Endocr. Metab. 88: 5353-5360, 2003. [PubMed: 14602773] [Full Text: https://doi.org/10.1210/jc.2002-021895]
Brinkmeier, M. L., Camper, S. A. Localization of somatostatin receptor genes on mouse chromosomes 2, 11, 12, 15, and 17: correlation with growth QTLs. Genomics 43: 9-14, 1997. [PubMed: 9226367] [Full Text: https://doi.org/10.1006/geno.1997.4781]
Buscail, L., Saint-Laurent, N., Chastre, E., Vaillant, J. C., Gespach, C., Capella, G., Kalthoff, H., Lluis, F., Vaysse, N., Susini, C. Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Res. 56: 1823-1827, 1996. [PubMed: 8620499]
Dorflinger, U., Pscherer, A., Moser, M., Rummele, P., Schule, R., Buettner, R. Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. Molec. Cell. Biol. 19: 3736-3747, 1999. [PubMed: 10207097] [Full Text: https://doi.org/10.1128/MCB.19.5.3736]
Filopanti, M., Ronchi, C., Ballare, E., Bondioni, S., Lania, A. G., Losa, M., Gelmini, S., Peri, A., Orlando, C., Beck-Peccoz, P., Spada, A. Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly. J. Clin. Endocr. Metab. 90: 4824-4828, 2005. [PubMed: 15914528] [Full Text: https://doi.org/10.1210/jc.2005-0132]
Greenwood, M. T., Robertson, L.-A., Patel, Y. C. Cloning of the gene encoding human somatostatin receptor 2: sequence analysis of the 5-prime-flanking promoter region. Gene 159: 291-292, 1995. [PubMed: 7622071] [Full Text: https://doi.org/10.1016/0378-1119(95)00059-f]
Guillermet, J., Saint-Laurent, N., Rochaix, P., Cuvillier, O., Levade, T., Schally, A. V., Pradayrol, L., Buscail, L., Susini, C., Bousquet, C. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc. Nat. Acad. Sci. 100: 155-160, 2003. [PubMed: 12490654] [Full Text: https://doi.org/10.1073/pnas.0136771100]
Patel, Y. C., Greenwood, M., Kent, G., Panetta, R., Srikant, C. B. Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation. Biochem. Biophys. Res. Commun. 192: 288-294, 1993. [PubMed: 8386508] [Full Text: https://doi.org/10.1006/bbrc.1993.1412]
Pscherer, A., Dorflinger, U., Kirfel, J., Gawlas, K., Ruschoff, J., Buettner, R., Schule, R. The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene. EMBO J. 15: 6680-6690, 1996. [PubMed: 8978694]
Raggi, C. C., Maggi, M., Renzi, D., Calabro, A., Bagnoni, M. L., Scaruffi, P., Tonini, G. P., Pazzagli, M., De Bernardi, B., Bernini, G., Serio, M., Orlando, C. Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome. J. Clin. Endocr. Metab. 85: 3866-3873, 2000. [PubMed: 11061551] [Full Text: https://doi.org/10.1210/jcem.85.10.6904]
Ren, S.-G., Taylor, J., Dong, J., Yu, R., Culler, M. D., Melmed, S. Functional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion. J. Clin. Endocr. Metab. 88: 4239-4245, 2003. [PubMed: 12970293] [Full Text: https://doi.org/10.1210/jc.2003-030303]
Yamada, Y., Stoffel, M., Espinosa, R., III, Xiang, K., Seino, M., Seino, S., Le Beau, M. M., Bell, G. I. Human somatostatin receptor genes: localization to human chromosomes 14, 17 and 22 and identification of simple tandem repeat polymorphisms. Genomics 15: 449-452, 1993. [PubMed: 8449518] [Full Text: https://doi.org/10.1006/geno.1993.1088]
Zatelli, M. C., Tagliati, F., Taylor, J. E., Rossi, R., Culler, M. D., degli Uberti, E. C. Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line TT. J. Clin. Endocr. Metab. 86: 2161-2169, 2001. [PubMed: 11344221] [Full Text: https://doi.org/10.1210/jcem.86.5.7489]
Zhang, C.-Y., Yokogoshi, Y., Yoshimoto, K., Fujinaka, Y., Matsumoto, K., Saito, S. Point mutation of the somatostatin receptor 2 gene in the human small cell lung cancer cell line COR-L103. Biochem. Biophys. Res. Commun. 210: 805-815, 1995. [PubMed: 7763254] [Full Text: https://doi.org/10.1006/bbrc.1995.1730]