Biology:Regucalcin

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Regucalcin is a protein that in humans is encoded by the RGN gene[1][2][3]

The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver, kidney and other tissues.[4][5][6][7] It may have an important role in calcium homeostasis. Studies in rats indicate that this protein may also play a role in aging, as it shows age-associated down-regulation. This gene is part of a gene cluster on chromosome Xp11.3-Xp11.23. Alternative splicing results in two transcript variants having different 5' UTRs, but encoding the same protein.[3]

Regucalcin is a proposed name for a calcium-binding protein that was discovered in 1978 [8][9][10][11] This protein is also known as Senescence Marker Protein-30 (SMP30).[12][13] Regucalcin differs from calmodulin and other Ca2+-related proteins as it does not contain an EF-hand motif of Ca2+-binding domain.[9][14] It may regulate the effect of Ca2+ on liver cell functions.[11] From many investigations, regucalcin has been shown to play a multifunctional role in many cell types as a regulatory protein in the intracellular signaling system.

Gene

Regucalcin and its gene (rgn) are identified in 16 species consisting of regucalcin family.[7][14] Regucalcin is greatly expressed in the liver of rats, although the protein is found in small amounts in other tissues and cells. The rat regucalcin gene consists of seven exons and six introns, and several consensus regulatory elements exist upstream of the 5’-flanking region.[15] The gene is localized on the proximal end of rat chromosome Xq11.1-12 and human Xp11.3-Xp11.23. AP-1, NFI-A1, RGPR-p117, and Wnt/β-catenin/TCF4 can bind to the promoter region of the rat regucalcin gene to mediate the Ca2+ and other signaling responses with various hormones and cytokines for transcriptional activation.[16]

Function

Regucalcin plays a pivotal role in the keep of intracellular Ca2+ homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum) and mitochondria of many cells. Regucalcin is localized in the cytoplasm, mitochondria, microsomes and nucleus. Regucalcin is translocated from cytoplasm to nucleus with hormone stimulation. Regucalcin has a suppressive effect on calcium signaling from the cytoplasm to the nucleus in the proliferative cells. Also, regucalcin has been demonstrated to transport into the nucleus of cells, and it can inhibit nuclear protein kinase, protein phosphatase, and deoxyribonucleic acid and ribonucleic acid synthesis. Regucalcin can control enhancement of cell proliferation due to hormonal stimulation. Moreover, regucalcin has been shown to have an inhibitory effect on aminoacyl t-RNA synthetase, a rate limiting enzyme at translational process of protein synthesis and an activatory effect on cystein protease and superoxide dismutase in liver and kidney cells.

Regucalcin is expressed in the neuron of brain tissues, and the decrease of brain regucalcin causes accumulation of calcium in the brain microsomes. Regucalcin has an inhibitory effect on protein kinase and protein phosphatase activity dependent on Ca signaling. Regucalcin has been shown to have an activatory effect on Ca pumping enzyme (Ca-ATPase) in heart sarcoplasmic reticulum. Regucalcin plays a role in the promotion of urinary calcium transport in the epithelial cells of kidney cortex. Overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells and normal rat kidney epithelial cells (NRK52E) induced by various signaling factors.

Thus, regucalcin plays a multifunctional role in the regulation of cell functions in liver, kidney cortex, heart and brain. Thus, regucalcin plays a pivotal role in keep of cell homeostasis and function.[17] Regucalcin plays a pivotal role as a suppressor protein for cell signaling systems in many cell types.

Pathophysiologic role

Overexpressing of regucalcin in rats (transgenic rats) has been shown to induce bone loss and hyperlipidemia with increasing age, indicating a pathophysiologic role. Regucalcin transgenic rat may be a useful tool as animal model in osteoporosis and hyperlipidemia.[18] Also, regucalcin/SMP30-knockout mice are known to induce a suppression in ascorbic acid biosynthesis. The disorder of regucalcin expression has been proposed to be induced cancer, brain function, heart injury, kidney failure, osteoporosis, and hyperlipidemia.[19][20] Regucalcin plays a novel role as a suppressor in carcinogenesis of human patients with various types of cancer including pancreatic cancer, breast cancer, hepatoma, and lung cancer.[21][22][19] Of note, it has been conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Regucalcin (RGN) was proposed to be a core gene (protein) with high priority of frailty biomarkers in order to ascertain their diagnostic, prognostic and therapeutic potential.[23] Notably, it has been shown that epigenetic modifications of survivin and regucalcin in non-small cell lung cancer tissues contribute to malignancy.[24]

References

  1. ↑ "Genomic cloning and chromosomal assignment of rat regucalcin gene". Molecular and Cellular Biochemistry 151 (2): 157–63. October 1995. doi:10.1007/BF01322338. PMID 8569761. 
  2. ↑ "Isolation of cDNA clone encoding human homologue of senescence marker protein-30 (SMP30) and its location on the X chromosome". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1263 (3): 249–52. September 1995. doi:10.1016/0167-4781(95)00120-6. PMID 7548213. 
  3. ↑ 3.0 3.1 "Entrez Gene: RGN regucalcin (senescence marker protein-30)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9104. 
  4. ↑ "Immunohistochemical demonstration of calcium-binding protein regucalcin in the tissues of rats: the protein localizes in liver and brain". Chemical & Pharmaceutical Bulletin 39 (6): 1601–3. June 1991. doi:10.1248/cpb.39.1601. PMID 1934180. 
  5. ↑ "Calcium administration stimulates the expression of calcium-binding protein regucalcin mRNA in rat liver". FEBS Letters 305 (2): 151–4. June 1992. doi:10.1016/0014-5793(92)80884-J. PMID 1618342. 
  6. ↑ "Tissue concentration of calcium-binding protein regucalcin in rats by enzyme-linked immunoadsorbent assay". Molecular and Cellular Biochemistry 122 (1): 65–8. May 1993. doi:10.1007/BF00925738. PMID 8350865. 
  7. ↑ 7.0 7.1 "The gene of Ca2+-binding protein regucalcin is highly conserved in vertebrate species". International Journal of Molecular Medicine 6 (2): 191–6. August 2000. doi:10.3892/ijmm.6.2.191. PMID 10891565. 
  8. ↑ "Purification of calcium binding substance from soluble fraction of normal rat liver". Chemical & Pharmaceutical Bulletin 26 (6): 1915–8. June 1978. doi:10.1248/cpb.26.1915. PMID 699201. 
  9. ↑ 9.0 9.1 "Properties of calcium-binding protein isolated from the soluble fraction of normal rat liver". Chemical & Pharmaceutical Bulletin 29 (2): 567–70. February 1981. doi:10.1248/cpb.29.567. PMID 7273253. 
  10. ↑ "Effect of Ca2+ and Zn2+ on 5'-nucleotidase activity in rat liver plasma membranes: Hepatic calcium-binding protein (regucalcin) reverses the Ca2+ effect". Chemical & Pharmaceutical Bulletin 36 (1): 321–325. January 1988. doi:10.1248/cpb.36.321. PMID 2837338. 
  11. ↑ 11.0 11.1 Yamaguchi M (1992). "A novel Ca2+-binding protein regucalcin and calcium inhibition. Regulatory role in liver cell function". Calcium Inhibition. Boca Raton: CRC Press. pp. 19–41. 
  12. ↑ "Purification of senescence marker protein-30 (SMP30) and its androgen-independent decrease with age in the rat liver". Biochimica et Biophysica Acta (BBA) - General Subjects 1116 (2): 122–8. April 1992. doi:10.1016/0304-4165(92)90108-7. PMID 1581340. 
  13. ↑ "Isolation of cDNA clone encoding rat senescence marker protein-30 (SMP30) and its tissue distribution". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1132 (3): 297–305. October 1992. doi:10.1016/0167-4781(92)90164-u. PMID 1420310. 
  14. ↑ 14.0 14.1 "Molecular cloning and sequencing of the cDNA coding for a calcium-binding protein regucalcin from rat liver". FEBS Letters 327 (3): 251–5. August 1993. doi:10.1016/0014-5793(93)80998-a. PMID 8348951. 
  15. ↑ "The 5' end sequences and exon organization in rat regucalcin gene". Molecular and Cellular Biochemistry 165 (2): 145–50. December 1996. doi:10.1007/bf00229476. PMID 8979263. 
  16. ↑ "The transcriptional regulation of regucalcin gene expression". Molecular and Cellular Biochemistry 346 (1–2): 147–71. January 2011. doi:10.1007/s11010-010-0601-8. PMID 20936536. 
  17. ↑ "Role of regucalcin in maintaining cell homeostasis and function (review)". International Journal of Molecular Medicine 15 (3): 371–89. March 2005. doi:10.3892/ijmm.15.3.371. PMID 15702226. 
  18. ↑ "Regucalcin and metabolic disorders: osteoporosis and hyperlipidemia are induced in regucalcin transgenic rats". Molecular and Cellular Biochemistry 341 (1–2): 119–33. August 2010. doi:10.1007/s11010-010-0443-4. PMID 20349117. 
  19. ↑ 19.0 19.1 Yamaguchi M (2017). The Role of Regucalcin in Cell Homeostasis and Disorder. New York: Nova Science Publishers. pp. 1–288. ISBN 978-3-319-39855-6. 
  20. ↑ Yamaguchi M, ed (2019). Regucalcin: Metabolic Regulation and Disease. New York: Nova Science Publishers. pp. 1–176. ISBN 978-1536161724. 
  21. ↑ "Involvement of regucalcin as a suppressor protein in human carcinogenesis: Insight into the gene therapy". Journal of Cancer Research and Clinical Oncology 141 (8): 133–1341. August 2015. doi:10.1007/s00432-014-1831-z. PMID 25230901. 
  22. ↑ "Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro". International Journal of Oncology 48 (5): 1955–1964. May 2016. doi:10.3892/ijo.2016.3409. PMID 26935290. 
  23. ↑ "Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases". Journal of Cancer Research and Clinical Oncology 47: 214–277. July 2018. doi:10.1016/j.arr.2018.07.004. PMID 30071357. 
  24. ↑ "Live and let die: epigenetic modifications of Survivin and Regucalcin in non-small cell lung cancer tissues contribute to malignancy". Clinical Epigenetics 11 (1): 157. November 2019. doi:10.1186/s13148-019-0770-6. PMID 31718698. 

Further reading



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