Stanniocalcin (originally named hypocalcin or teleocalcin or parathyrin)[1] is a family of hormones which regulate calcium and phosphate balance in the body. The first stanniocalcin discovered was from fish and was identified as the principal calcium-reducing (hypocalcaemic) factor.[2] It was isolated from special organs in fish called corpuscles of Stannius, hence the name stanniocalcin. Chemically, stanniocalcins are glycosylated proteins (i.e. proteins containing carbohydrate, or glycoproteins) having a molecular mass of 50 kDa. They exist in molecular pairs (homodimers) and are joined together by disulfide linkage. Stanniocalcins are made up of approximately 250 amino acids.[3]

Discovery

In 1839, the German anatomist Hermann Friedrich Stannius discovered a pair of novel structures inside the kidneys of sturgeon and bony fishes. He believed that they were a kind of adrenal gland (found in mammals) in these fishes. In 1896, the French physiologist A. Petit demonstrated that removal of one of the structures led to degeneration of the other. He suggested that these structures were endocrine organs. In 1908, the Italian zoologist Ercole Giacomini was the first to describe that these structures were present only in fishes which lack a parathyroid gland. He distinguished and named them "posterior interrenal" from the anterior portion of the kidney, which he named "anterior interrenal".[4] A French Physiologist M. Fontaine reported that the corpuscles were responsible for controlling calcium level in the blood. In 1971 Peter K.T. Pang of Yale University showed in the male killifish, Fundulus heteroclitus, that the corpuscles control calcium metabolism. He found that removal of the corpuscle led to development of kidney stone and increase in serum calcium level.[5] By the mid 1970s, it was confirmed that the corpuscles secrete a factor that can reduce calcium level, similar to calcitonin but completely different. and Pang gave the prospective name "hypocalcin".[6][7] The chemical compound was isolated in 1986 from sockeye salmon (Oncorhynchus nerka), and since it was from a teleost, it was called "teleocalcin".[2][8] A better isolation was reported in 1988 from different species, including European eel, tilapia, goldfish, and carp. It was realised that both hypocalcin and teleocalcin are the same.[3] It was conclusively shown that the isolated compound was the factor that reduces calcium level in these fishes.[9][10] In 1990, the exact chemical composition and biosynthesis war worked out, and was given the name "stanniocalcin" as it was found to be exclusively produced by the corpuscles of Stannius.[11] The complete amino acid sequence was described in 1995.[12]

Structure

Stanniocalcin is a glycoprotein that exists in a homodimer, i.e. two similar peptide molecules combined. Each single molecule is made up of 179 amino acids. The peptide sequence is characterised by the presence of 11 half-Cys residues and one N-linked glycosylation site.[12] The actual amino acid sequence and total length differ between species, hence, the molecular weight. In most species it is 54 kDa in size.[3] While it is only 44 kDa in Atlantic salmon.[13] In chum salmon, the homodimer in joined by a single intermonomeric disulfide bond at Cys169. Each monomer in turn contains five intramonomeric disulfide bonds formed between Cys12-Cys26, Cys21-Cys41, Cys32-Cys81, Cys65-Cys95, and Cys102-Cys137.[14] Its synthesis is regulated by the expression of STC (stannioclacin) mRNA. The STC mRNA sequence varies from species to species. For example, in salmon it is approximately 2 kilobases in length and encodes a primary translation product of 256 amino acids. The first 33 residues comprise the pre-pro (inactive form) region of the hormone, whereas the remaining 223 residues make up the mature form of the hormone. One N-linked, glycosylation consensus sequence was identified in the protein coding region as well as an odd number of half cysteine residues, the latter of which would allow for interchain bonding or dimerisation of monomeric subunits.[15]

Function

In bony fishes, stanniocalcin is the principal hormone that regulate calcium level. Even though other calcium-decreasing hormone, calcitonin, is also present, these fishes require more efficient hormone as calcium rapidly enters into their blood through their gills and intestinal wall. Hence, the target sites of stanniocalsin are gill and intestine, where uptake (absorption) of calcium is directly inhibited.[16] Increase in the serum calcium triggers the release of stanniocalcin. Unlike calcitonin, it also regulates phosphate level.[17] It inhibits excretion of phosphate from the kidney.[1]

Variation in other animals

Stanniocalcin was also detected in mammals. In mammals there are two variant forms, STC1, which is fundamentally similar to fish stanniocalcin, and STC2, which is more different in structure and function. In invertebrates, freshwater leeches are found to contain the hormone. In leeches it is produced in the fat cells (adipocytes).[18]

STC1

STC1 was discovered in 1995 from human kidney. It was demonstrated that human kidney extract produced the same calcium inhibitory action when injected in a fish.[19] The gene that produce STC1, STC1 is located in the short arm of human chromosome 8 (position p21.2). STC1 mRNA is formed in heart, lung, liver, adrenal gland, prostate, and ovary, indicating that these are the sites of synthesis. Ovary contains the highest level of STC1 mRNA. Fish stanniocalcin and mammalian STC1 are closely related, and are about 50% similar in their structure.[20] They are both responsible for calcium and phosphate balance.[21] In mammals the predominant function of STC1 is to activate phosphate reabsorption in the small intestine and proximal tubules of the kidney.[22]

STC2

STC2 was discovered from the human DNA database.[23] In human STC2 is produced by STC2 gene which is located in the long arm of human chromosome 5 (position q35.1). It is very different from STC1 and show only 34% similarity. STC2 mRNA is found in pancreas, kidney, spleen, and skeletal muscles.[20]

Medical importance

Mammalian stanniocalcins are known to be related to cancer development, such as breast and ovarian cancers. In these cancers, both STC1 and STC2 are excessively produced. Their location in chromosomes are the sites of genes for tumour formation.[22] In breast cancer the elevated hormones correspond to increased estrogen receptors. Increased STC1 is specifically linked to other cancer types, including leukemia, colorectal cancer, carcinoma, and lung cancer.[24] STC2 is related to cervical cancer,[25] and ovarian cancer.[26]

References

  1. 1 2 Suzuki, Nobuo (2015). "Stanniocalcin". In Takei, Yoshio; Ando, Hironori; Tsutsui, Kazuyoshi (eds.). Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research. Oxford (UK): Academic Press. pp. 247–249. ISBN 978-0-12-801067-9.
  2. 1 2 Wagner, GF; Hampong, M; Park, CM; Copp, DH (1986). "Purification, characterization, and bioassay of teleocalcin, a glycoprotein from salmon corpuscles of Stannius". General and Comparative Endocrinology. 63 (3): 481–91. doi:10.1016/0016-6480(86)90149-8. PMID 3557071.
  3. 1 2 3 Lafeber, FP; Hanssen, RG; Choy, YM; Flik, G; Herrmann-Erlee, MP; Pang, PK; Bonga, SE (1988). "Identification of hypocalcin (teleocalcin) isolated from trout Stannius corpuscles" (PDF). General and Comparative Endocrinology. 69 (1): 19–30. doi:10.1016/0016-6480(88)90048-2. hdl:2066/16625. PMID 3360288. S2CID 8583927.
  4. ↑ Nadkarni, V. B.; Gorbman, Aubrey (1966). "Structure of the corpuscle of Stannius in normal and radiothyroidectomized chinook fingerlings and spawning Pacific salmon". Acta Zoologica. 47 (1–2): 61–66. doi:10.1111/j.1463-6395.1966.tb00741.x.
  5. ↑ Pang, Peter K. T. (1971). "The relationship between corpuscles of Stannius and serum electrolyte regulation in killifish, Fundulus heteroclitus". Journal of Experimental Zoology. 178 (1): 1–8. doi:10.1002/jez.1401780102. PMID 5094234.
  6. ↑ Pang, PK; Pang, RK (1974). "Environmental calcium and hypocalcin activity in the Stannius corpuscles of the channel catfish, Ictalurus punctatus (Rafinesque)". General and Comparative Endocrinology. 23 (2): 239–241. doi:10.1016/0016-6480(74)90133-6. PMID 4837805.
  7. ↑ Olivereau, M; Olivereau, J (1978). "Prolactin, hypercalcemia and corpuscles of Stannius in seawater eels". Cell and Tissue Research. 186 (1): 81–96. doi:10.1007/bf00219656. PMID 627014. S2CID 24457863.
  8. ↑ Wagner, Graham F.; Friesen, Henry G. (1989). "Studies on the structure and physiology of salmon teleocalcin". Fish Physiology and Biochemistry. 7 (1–6): 367–374. doi:10.1007/BF00004730. PMID 24221795. S2CID 22823404.
  9. ↑ Lafeber, FP; Flik, G; Wendelaar Bonga, SE; Perry, SF (1988). "Hypocalcin from Stannius corpuscles inhibits gill calcium uptake in trout". The American Journal of Physiology. 254 (6 Pt 2): R891-6. doi:10.1152/ajpregu.1988.254.6.R891. hdl:2066/16626. PMID 3381914. S2CID 5032975.
  10. ↑ Lafeber, FP; Perry, SF (1988). "Experimental hypercalcemia induces hypocalcin release and inhibits branchial Ca2+ influx in freshwater trout". General and Comparative Endocrinology. 72 (1): 136–143. doi:10.1016/0016-6480(88)90189-x. PMID 3181737.
  11. ↑ Flik, G; Labedz, T; Neelissen, JA; Hanssen, RG; Wendelaar Bonga, SE; Pang, PK (1990). "Rainbow trout corpuscles of Stannius: stanniocalcin synthesis in vitro". The American Journal of Physiology. 258 (5 Pt 2): R1157-1164. doi:10.1152/ajpregu.1990.258.5.R1157. PMID 2337196.
  12. 1 2 Yamashita, Kunihiko; Koide, Yoshio; Itoh, Hiromichi; Kawada, Naoki; Kawauchi, Hiroshi (1995). "The complete amino acid sequence of chum salmon stanniocalcin, a calcium-regulating hormone in teleosts". Molecular and Cellular Endocrinology. 112 (2): 159–167. doi:10.1016/0303-7207(95)03590-4. PMID 7489819. S2CID 39537422.
  13. ↑ Wagner, GF; Jaworski, EM; Haddad, M (1998). "Stanniocalcin in the seawater salmon: structure, function, and regulation". The American Journal of Physiology. 274 (4 Pt 2): R1177-1185. doi:10.1152/ajpregu.1998.274.4.R1177. PMID 9575986.
  14. ↑ Hulova, Irena; Kawauchi, Hiroshi (1999). "Assignment of disulfide linkages in chum salmon stanniocalcin". Biochemical and Biophysical Research Communications. 257 (2): 295–299. doi:10.1006/bbrc.1999.0466. PMID 10198206.
  15. ↑ Wagner, Graham F.; Dimattia, Gabriel E.; Davie, James R.; Copp, D.Harold; Friesen, Henry G. (1992). "Molecular cloning and cDNA sequence analysis of coho salmon stanniocalcin". Molecular and Cellular Endocrinology. 90 (1): 7–15. doi:10.1016/0303-7207(92)90095-N. PMID 1363790. S2CID 46389908.
  16. ↑ Flik, G (1990). "Hypocalcin physiology". Progress in Clinical and Biological Research. 342: 578–585. PMID 2200039.
  17. ↑ Wagner, GF; Jaworski, EM; Haddad, M (1998). "Stanniocalcin in the seawater salmon: structure, function, and regulation". The American Journal of Physiology. 274 (4 Pt 2): R1177-1185. doi:10.1152/ajpregu.1998.274.4.R1177. PMID 9575986.
  18. ↑ Tanega, Cherry; Radman, Dennis P.; Flowers, Bree; Sterba, Thomas; Wagner, Graham F. (2004). "Evidence for stanniocalcin and a related receptor in annelids". Peptides. 25 (10): 1671–1679. doi:10.1016/j.peptides.2004.02.024. PMID 15476934. S2CID 22476519.
  19. ↑ Wagner, GF; Guiraudon, CC; Milliken, C; Copp, DH (1995). "Immunological and biological evidence for a stanniocalcin-like hormone in human kidney". Proceedings of the National Academy of Sciences of the United States of America. 92 (6): 1871–1875. Bibcode:1995PNAS...92.1871W. doi:10.1073/pnas.92.6.1871. PMC 42384. PMID 7892193.
  20. 1 2 Ishibashi, Kenichi; Imai, Masashi (2002). "Prospect of a stanniocalcin endocrine/paracrine system in mammals". American Journal of Physiology. 282 (3): F367–F375. doi:10.1152/ajprenal.00364.2000. PMID 11832417.
  21. ↑ Madsen, KL; Tavernini, MM; Yachimec, C; Mendrick, DL; Alfonso, PJ; Buergin, M; Olsen, HS; Antonaccio, MJ; Thomson, AB; Fedorak, RN (1998). "Stanniocalcin: a novel protein regulating calcium and phosphate transport across mammalian intestine". The American Journal of Physiology. 274 (1 Pt 1): G96-102. doi:10.1152/ajpgi.1998.274.1.G96. PMID 9458778.
  22. 1 2 Yeung, B.H.Y.; Law, A.Y.S.; Wong, Chris K.C. (2012). "Evolution and roles of stanniocalcin". Molecular and Cellular Endocrinology. 349 (2): 272–280. doi:10.1016/j.mce.2011.11.007. PMID 22115958. S2CID 10848821.
  23. ↑ Wagner, Graham F.; Dimattia, Gabriel E. (2006). "The stanniocalcin family of proteins". Journal of Experimental Zoology Part A: Comparative Experimental Biology. 305A (9): 769–780. doi:10.1002/jez.a.313. PMID 16902962.
  24. ↑ Chu, S.-J.; Zhang, J.; Zhang, R.; Lu, W.-W.; Zhu, J.-S. (2015). "Evolution and functions of stanniocalcins in cancer". International Journal of Immunopathology and Pharmacology. 28 (1): 14–20. doi:10.1177/0394632015572745. PMID 25816401. S2CID 11212156.
  25. ↑ Wang, Yuxia; Gao, Ying; Cheng, Hairong; Yang, Guichun; Tan, Wenhua (2015). "Stanniocalcin 2 promotes cell proliferation and cisplatin resistance in cervical cancer". Biochemical and Biophysical Research Communications. 466 (3): 362–368. doi:10.1016/j.bbrc.2015.09.029. PMID 26361149.
  26. ↑ Wu, Jingjing; Lai, Maode; Shao, Changshun; Wang, Jian; Wei, Jian-Jun (2015). "STC2 overexpression mediated by HMGA2 is a biomarker for aggressiveness of high-grade serous ovarian cancer". Oncology Reports. 34 (3): 1494–502. doi:10.3892/or.2015.4120. PMC 6918813. PMID 26165228.
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