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HGNC Approved Gene Symbol: SST
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38) : 3:187,668,912-187,670,394 (from NCBI)
The somatostatin precursor protein is processed into several peptide hormones, including somatostatin-14, somatostatin-28, and neuronostatin, that initiate cell signaling via surface receptors (Shen et al., 1982; Samson et al., 2008).
Using an anglerfish somatostatin probe, Shen et al. (1982) cloned SST from a human pancreatic somatostatinoma cDNA library. The deduced 116-amino acid precursor protein has a calculated molecular mass of 12.7 kD. It has an N-terminal signal sequence, and the C-terminal 28 or 14 amino acids are proteolytically released as mature somatostatin-28 or somatostatin-14 peptides, respectively. Human somatostatin-28 is identical to somatostatin-28 isolated from porcine and ovine species. Northern blot analysis detected a 750-bp transcript in pancreatic somatostatinoma cells.
Samson et al. (2008) identified neuronostatin, which is processed from the N-terminal end of the somatostatin precursor protein, just after the signal peptide. Neuronostatin isoforms of 6, 11, 13, and 19 residues were predicted. Mature neuronostatin was predicted to be amidated because of the presence of a conserved C-terminal glycine. All 19 neuronostatin residues are identical among 6 mammalian species, including human, and differ from rat and mouse neuronostatin at only 1 residue near the C terminus. Radioimmunoassays detected neuronostatin in diverse rat tissues, with highest levels in spleen and pancreas, followed by cerebrum and hypothalamus. Immunohistochemical analysis detected cytoplasmic neuronostatin staining that overlapped that of somatostatin in pancreas, small intestine, and gastric parietal cells.
Yacubova and Komuro (2002) examined the effects of somatostatin in cerebellar granule cells of early postnatal mice, because these cells express all 5 types of somatostatin receptors before the initiation of their migration. Yacubova and Komuro (2002) demonstrated that somatostatin has opposite and stage-specific effects on the migration of cerebellar granule cells. Activation of somatostatin receptors increases the rate of granule cell migration near their birthplace, but decreases the rate near their final destination. Furthermore, somatostatin enhances the size and frequency of spontaneous calcium fluctuations in the early phase of migration, whereas it eliminates spike-like calcium transients in the late phase. Somatostatin-induced changes at both early and late phases are reversed by a blockade of potassium channel activity. Yacubova and Komuro (2002) concluded that somatostatin may provide an essential cue for accelerating the movement of granule cells in the early phase and for terminating the movement in the late phase through altering intracellular calcium concentrations and potassium channel activity.
Saito et al. (2005) found that somatostatin modulated the proteolytic degradation of beta-amyloid (APP; 104760) catalyzed by neprilysin (120520) both in vitro and in vivo. Primary cortical neurons treated with somatostatin showed an upregulation of neprilysin activity and a reduction in A-beta-42. Sst-null mice showed a 1.5-fold increase in hippocampal A-beta-42, but not A-beta-40. Saito et al. (2005) noted that expression of somatostatin in the brain declines with normal aging, and postulated that a similar decrease in neprilysin activity with gradual accumulation of pathogenic beta-amyloid aggregates may underlie late-onset Alzheimer disease (104300).
Samson et al. (2008) used recombinant human neuronostatin-19 and recombinant rat neuronostatin-13 to study neuronostatin function. They found that neuronostatin induced Fos (164810) expression in mouse gastrointestinal tissues and anterior pituitary and in rat cerebellum and hippocampus. In vitro treatment with neuronostatin induced migration of rat cerebellar granule cells in a growth cone turning assay and elicited depolarization of rat paraventricular neurons in hypothalamic slices. Intracerebral injection of neuronostatin in rats increased blood pressure and suppressed food and water intake. In human gastric tumor cells, neuronostatin induced Fos expression, stimulated serum response element (SRE) reporter activity, and promoted cell proliferation. Neuronostatin did not regulate growth hormone release in cultured rat anterior pituitary cells or activate any human somatostatin receptor tested.
Using isolated perfused rat hearts and cultured rat and mouse primary cardiomyocytes, Vainio et al. (2012) showed that neuronostatin inhibited endothelin-1 (EDN1; 131240)-induced left ventricular contractility, but that it had no effect on contractility itself. At low concentrations, neuronostatin treatment induced phosphorylation of p38 MAP kinase (MAPK14; 600289) and Jnk (see MAPK8; 601158) in rat heart. At higher concentrations, neuronostatin induced necrosis, but not apoptosis, in isolated cardiomyocytes.
Naylor et al. (1983) assigned the somatostatin gene to chromosome 3 by analyzing somatic cell hybrids with a polymorphic gene probe. By in situ hybridization combined with high resolution cytogenetics, Zabel et al. (1983) assigned the amylase gene to 1p21, the POMC gene to 2p23, and the somatostatin gene to 3q28. In studies of mouse-Chinese hamster hybrids by Southern blot analysis, Lalley et al. (1987) mapped the gene for somatostatin (Smst) to mouse chromosome 16. Polymorphic restriction sites for BamHI and EcoRI, associated with the SST locus, were described by Lucarelli et al. (1988).
In a study of Helicobacter infection (see 600263) and the immune response regulation of acid secretion, Zavros et al. (2003) demonstrated that treatment with the Th1 cytokine Ifng (147570) induced gastritis, increased gastrin (137250), and decreased somatostatin in mice, recapitulating changes seen with Helicobacter infection. In contrast, the Th2 cytokine Il4 (147780) increased somatostatin levels and suppressed gastrin expression and secretion. Il4 pretreatment prevented gastritis in infected wildtype but not in somatostatin-null mice. Immunofluorescence confirmed the presence of Il4 receptors (IL4R; 147781) on gastric somatostatin-secreting cells (D cells), and Il4 stimulated somatostatin release from primary D-cell cultures. Treatment of mice chronically infected with H. felis with a somatostatin analog resolved the inflammation. Zavros et al. (2003) concluded that IL4 resolves inflammation in the stomach by stimulating the release of somatostatin from gastric D cells.
Lalley, P. A., Sakaguchi, A. Y., Eddy, R. L., Honey, N. H., Bell, G. I., Shen, L.-P., Rutter, W. J., Jacobs, J. W., Heinrich, G., Chin, W. W., Naylor, S. L. Mapping polypeptide hormone genes in the mouse: somatostatin, glucagon, calcitonin, and parathyroid hormone. Cytogenet. Cell Genet. 44: 92-97, 1987. [PubMed: 2882956] [Full Text: https://doi.org/10.1159/000132350]
Lucarelli, P., Mantuano, E., Schiattarella, E., Palmarino, R. Evidence for linkage equilibrium between two RFLPs associated with the human SST locus. Hum. Genet. 78: 291-292, 1988. [PubMed: 2894349] [Full Text: https://doi.org/10.1007/BF00291681]
Naylor, S. L., Sakaguchi, A. Y., Shen, L.-P., Bell, G. I., Rutter, W. J., Shows, T. B. Polymorphic human somatostatin gene is located on chromosome 3. Proc. Nat. Acad. Sci. 80: 2686-2689, 1983. [PubMed: 6133281] [Full Text: https://doi.org/10.1073/pnas.80.9.2686]
Saito, T., Iwata, N., Tsubuki, S., Takaki, Y., Takano, J., Huang, S.-M., Suemoto, T., Higuchi, M., Saido, T. C. Somatostatin regulates brain amyloid beta-peptide A-beta-42 through modulation of proteolytic degradation. Nature Med. 11: 434-439, 2005. [PubMed: 15778722] [Full Text: https://doi.org/10.1038/nm1206]
Samson, W. K., Zhang, J. V., Avsian-Kretchmer, O., Cui, K., Yosten, G. L. C., Klein, C., Lyu, R.-M., Wang, Y. X., Chen, X. Q., Yang, J., Price, C. J., Hoyda, T. D., Ferguson, A. V., Yuan, X., Chang, J. K., Hsueh, A. J. W. Neuronostatin encoded by the somatostatin gene regulates neuronal, cardiovascular, and metabolic functions. J. Biol. Chem. 283: 31949-31959, 2008. [PubMed: 18753129] [Full Text: https://doi.org/10.1074/jbc.M804784200]
Shen, L.-P., Pictet, R. L., Rutter, W. J. Human somatostatin I: sequencing of the cDNA. Proc. Nat. Acad. Sci. 79: 4575-4579, 1982. [PubMed: 6126875] [Full Text: https://doi.org/10.1073/pnas.79.15.4575]
Shen, L.-P., Rutter, W. J. Sequence of the human somatostatin I gene. Science 224: 168-171, 1984. [PubMed: 6142531] [Full Text: https://doi.org/10.1126/science.6142531]
Vainio, L., Perjes, A., Ryti, N., Magga, J., Alakoski, T., Serpi, R., Kaikkonen, L., Piuhola, J., Szokodi, I., Ruskoaho, H., Kerkela, R. Neuronostatin, a novel peptide encoded by somatostatin gene, regulates cardiac contractile function and cardiomyocyte survival. J. Biol. Chem. 287: 4572-4580, 2012. [PubMed: 22170057] [Full Text: https://doi.org/10.1074/jbc.M111.289215]
Yacubova, E., Komuro, H. Stage-specific control of neuronal migration by somatostatin. Nature 415: 77-81, 2002. [PubMed: 11780120] [Full Text: https://doi.org/10.1038/415077a]
Zabel, B. U., Naylor, S. L., Sakaguchi, A. Y., Bell, G. I., Shows, T. B. High-resolution chromosomal localization of human genes for amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1) by in situ hybridization. Proc. Nat. Acad. Sci. 80: 6932-6936, 1983. [PubMed: 6196780] [Full Text: https://doi.org/10.1073/pnas.80.22.6932]
Zavros, Y., Rathinavelu, S., Kao, J. Y., Todisco, A., Del Valle, J., Weinstock, J. V., Low, M. J., Merchant, J. L. Treatment of Helicobacter gastritis with IL-4 requires somatostatin. Proc. Nat. Acad. Sci. 100: 12944-12949, 2003. [PubMed: 14555768] [Full Text: https://doi.org/10.1073/pnas.2135193100]