Alternative titles; symbols
HGNC Approved Gene Symbol: STC1
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38): 8:23,841,929-23,854,806 (from NCBI)
Mammalian stanniocalcin-1 is a glycoprotein that has been implicated in various biologic processes including angiogenesis, bone and muscle development, and cellular metabolism (summary by Nguyen et al., 2009).
Olsen et al. (1996) isolated a human cDNA clone encoding the mammalian homolog of STC. Human STC was found to be 247 amino acids long and to share 73% amino acid sequence similarity with fish STC. Polyclonal antibodies to recombinant human STC localized to a distinct cell type in the nephron tubule, suggesting kidney as a possible site of synthesis. Recombinant human STC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat.
Independently, Chang et al. (1995) isolated human STC cDNAs. Using Northern blot analysis, they found that STC is expressed as a 4-kb mRNA and a less abundant 2-kb mRNA in several human tissues, with the strongest expression in ovary, prostate, and thyroid. In human cell cultures, STC mRNA expression was positively regulated by extracellular calcium in the medium.
Varghese et al. (1998) determined that the predicted mouse and human proteins are 96% identical. In situ hybridization to mouse ovaries revealed that Stc mRNA was present in the thecal-interstitial cells of the ovarian stroma. Using immunohistochemistry, the authors found that STC protein was present in the stroma, the corpora lutea, and oocytes of the developing follicle. Varghese et al. (1998) suggested that STC may act as a signaling molecule between the thecal-interstitial cell compartment and the corpus luteum and oocyte.
By Western blot analysis, Jellinek et al. (2000) showed that STC1 is a secreted 31-kD doublet protein and STC2 (603665) is a secreted 32-kD protein. Unlike STC1, STC2 is not stored intracellularly but undergoes constitutive secretion. Autoradiographic analysis determined that STC1 is a 35-kD secreted protein that is phosphorylated by protein kinase C (see 600448) exclusively on serine residues. Jellinek et al. (2000) suggested that phosphorylation of STCs may be an important means of regulating their activity in calcium and phosphate homeostasis.
Varghese et al. (1998) reported that the mouse and human STC1 genes contain 4 exons and span approximately 13 kb.
Chang et al. (1998) found that there is a polymorphic CAG trinucleotide repeat complex in the 5-prime untranslated region of the STC mRNA and a smaller CAG repeat in the 3-prime untranslated region.
By fluorescence in situ hybridization, Chang et al. (1998) mapped the STC1 gene to chromosome 8p21-p11.2.
Stanniocalcin (STC) is a calcium-regulated hormone in bony fishes. The hormone was so named because it is synthesized by the corpuscles of Stannius, endocrine glands that are associated with the kidneys of all fishes with a bony skeleton. The primary function of STC in fishes is the prevention of hypercalcemia; Olsen et al. (1996) noted that a rise in serum calcium levels is the primary stimulus for secretion. Upon release into the circulation, STC lowers calcium transport by the gills, thereby reducing its rate of influx from the environment into the extracellular compartment. A second equally important action of STC is stimulation of phosphate reabsorption by renal proximal tubules. The consequence of this renal effect is increased levels of plasma phosphate, which combines with excess calcium and promotes its disposal into bone and scales. Wagner et al. (1995) found evidence of STC immunoreactivity in human kidney and serum, suggesting the existence of the hormone in mammals.
Zhang et al. (1998) reported a constitutive expression of STC in terminally differentiated neurons. Zhang et al. (2000) showed that exposure of human neural-crest-derived cell line Paju to hypercalcemic culture medium induced expression of STC. Treatment of Paju cells with recombinant human STC increased their uptake of inorganic phosphate. Paju cells expressing STC by cDNA transfection displayed increased resistance to ischemic challenge and to elevated intracellular free calcium induced by treatment with thapsigargin. An upregulated and redistributed expression of STC was observed in neurons surrounding the core of acute infarcts in human and rat brains. Given that mobilization and influx of calcium is considered a main neurotoxic mechanism following ischemia, their results suggested that the altered expression of STC contributes to the protection of cerebral neurons against hypoxic/ischemic damage. Manipulation of the STC expression may therefore offer a therapeutic approach to limit the injury after ischemic brain insults.
Bell et al. (2001) determined that STC1 was 1 of several transcripts upregulated by umbilical vein endothelial cells during capillary morphogenesis in 3-dimensional collagen matrices.
Nguyen et al. (2009) noted that Stc1 -/- mice have no obvious phenotype; however, they found that Stc1 -/- mouse embryonic fibroblasts (MEFs) grown at low density had a survival advantage over wildtype MEFs following exposure to peroxide or grown in an atmosphere of 20% oxygen, which normally induces oxidative stress. In wildtype MEFs, oxidative stress caused elevated Stc1 levels, which was abolished by pharmacologic inhibition of Mek (see MAP2K1, 176872) and therefore Erk1 (MAPK3; 601795)/ Erk2 (MAPK1; 176948) activation. Stc1 -/- MEFs had elevated levels of Mek and Erk1/Erk2 compared with wildtype MEFs, and these levels were reduced by stable expression of exogenous STC1 in Stc1 -/- MEFs. Pharmacologic inhibition of Mek restored sensitivity of Stc1 -/- MEFs to oxidative stress. Conversely, peroxide-induced Stc1 expression in wildtype cells was abolished by inhibition of Erk1/Erk2 activation. Nguyen et al. (2009) concluded that Erk1/Erk2 signaling upregulates Stc1 expression, which in turn downregulates the level of activated Mek and consequently prosurvival Erk1/Erk2 signaling in a negative feedback loop during oxidative stress.
Bell, S. E., Mavila, A., Salazar, R., Bayless, K. J., Kanagala, S., Maxwell, S. A., Davis, G. E. Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J. Cell Sci. 114: 2755-2773, 2001. [PubMed: 11683410] [Full Text: https://doi.org/10.1242/jcs.114.15.2755]
Chang, A. C.-M., Janosi, J., Hulsbeek, M., de Jong, D., Jeffrey, K. J., Noble, J. R., Reddel, R. R. A novel human cDNA highly homologous to the fish hormone stanniocalcin. Molec. Cell. Endocr. 112: 241-247, 1995. [PubMed: 7489828] [Full Text: https://doi.org/10.1016/0303-7207(95)03601-3]
Chang, A. C.-M., Jeffrey, K. J., Tokutake, Y., Shimamoto, A., Neumann, A. A., Dunham, M. A., Cha, J., Sugawara, M., Furuichi, Y., Reddel, R. R. Human stanniocalcin (STC): genomic structure, chromosomal localization, and the presence of CAG trinucleotide repeats. Genomics 47: 393-398, 1998. [PubMed: 9480753] [Full Text: https://doi.org/10.1006/geno.1997.5120]
Jellinek, D. A., Chang, A. C., Larsen, M. R., Wang, X., Robinson, P. J., Reddel, R. R. Stanniocalcin 1 and 2 are secreted as phosphoproteins from human fibrosarcoma cells. Biochem. J. 350: 453-461, 2000. [PubMed: 10947959]
Nguyen, A., Chang, A. C. M., Reddel, R. R. Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress. Oncogene 28: 1982-1992, 2009. [PubMed: 19347030] [Full Text: https://doi.org/10.1038/onc.2009.65]
Olsen, H. S., Cepeda, M. A., Zhang, Q.-Q., Rosen, C. A., Vozzolo, B. L., Wagner, G. F. Human stanniocalcin: a possible hormonal regulator of mineral metabolism. Proc. Nat. Acad. Sci. 93: 1792-1796, 1996. [PubMed: 8700837] [Full Text: https://doi.org/10.1073/pnas.93.5.1792]
Varghese, R., Wong, C. K. C., Deol, H., Wagner, G. F., DiMattia, G. E. Comparative analysis of mammalian stanniocalcin genes. Endocrinology 139: 4714-4725, 1998. [PubMed: 9794484] [Full Text: https://doi.org/10.1210/endo.139.11.6313]
Wagner, G. F., Guiraudon, C. C., Milliken, C., Copp, D. H. Immunological and biological evidence for a stanniocalcin-like hormone in human kidney. Proc. Nat. Acad. Sci. 92: 1871-1875, 1995. [PubMed: 7892193] [Full Text: https://doi.org/10.1073/pnas.92.6.1871]
Zhang, K., Lindsberg, P. J., Tatlisumak, T., Kaste, M., Olsen, H. S., Andersson, L. C. Stanniocalcin: a molecular guard of neurons during cerebral ischemia. Proc. Nat. Acad. Sci. 97: 3637-3642, 2000. [PubMed: 10725397] [Full Text: https://doi.org/10.1073/pnas.97.7.3637]
Zhang, K., Westberg, J. A., Paetau, A., von Boguslawsky, K., Lindsberg, P., Erlander, M., Guo, H., Su, J., Olsen, H. S., Andersson, L. C. High expression of stanniocalcin in differentiated brain neurons. Am. J. Path. 153: 439-445, 1998. [PubMed: 9708804] [Full Text: https://doi.org/10.1016/S0002-9440(10)65587-3]