Regucalcin

Regucalcin is a protein that in humans is encoded by the RGN gene[5][6][7]

RGN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRGN, GNL, HEL-S-41, RC, SMP30, regucalcin
External IDsOMIM: 300212 MGI: 108024 HomoloGene: 3437 GeneCards: RGN
EC number3.1.1.17
Orthologs
SpeciesHumanMouse
Entrez

9104

19733

Ensembl

ENSG00000130988

ENSMUSG00000023070

UniProt

Q15493

Q64374

RefSeq (mRNA)

NM_001282848
NM_001282849
NM_004683
NM_152869

NM_009060

RefSeq (protein)

NP_001269777
NP_001269778
NP_004674
NP_690608

NP_033086

Location (UCSC)Chr X: 47.08 – 47.09 MbChr X: 20.42 – 20.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver, kidney and other tissues.[8][9][10][11] 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.[7]

Regucalcin is a proposed name for a calcium-binding protein that was discovered in 1978 [12][13][14][15] This protein is also known as Senescence Marker Protein-30 (SMP30).[16][17] Regucalcin differs from calmodulin and other Ca2+-related proteins as it does not contain an EF-hand motif of Ca2+-binding domain.[13][18] It may regulate the effect of Ca2+ on liver cell functions.[15] 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.[11][18] 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.[19] 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.[20]

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.[21] 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.[22] 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.[23][24] 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.[25][26][23] 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.[27] Notably, it has been shown that epigenetic modifications of survivin and regucalcin in non-small cell lung cancer tissues contribute to malignancy.[28]

References
  1. GRCh38: Ensembl release 89: ENSG00000130988 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000023070 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Shimokawa N, Matsuda Y, Yamaguchi M (October 1995). "Genomic cloning and chromosomal assignment of rat regucalcin gene". Molecular and Cellular Biochemistry. 151 (2): 157–63. doi:10.1007/BF01322338. PMID 8569761. S2CID 20648596.
  6. Fujita T, Mandel JL, Shirasawa T, Hino O, Shirai T, Maruyama N (September 1995). "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. doi:10.1016/0167-4781(95)00120-6. PMID 7548213.
  7. "Entrez Gene: RGN regucalcin (senescence marker protein-30)".
  8. Yamaguchi M, Isogai M, Kato S, Mori S (June 1991). "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. doi:10.1248/cpb.39.1601. PMID 1934180.
  9. Shimokawa N, Yamaguchi M (June 1992). "Calcium administration stimulates the expression of calcium-binding protein regucalcin mRNA in rat liver". FEBS Letters. 305 (2): 151–4. doi:10.1016/0014-5793(92)80884-J. PMID 1618342. S2CID 24974683.
  10. Yamaguchi M, Isogai M (May 1993). "Tissue concentration of calcium-binding protein regucalcin in rats by enzyme-linked immunoadsorbent assay". Molecular and Cellular Biochemistry. 122 (1): 65–8. doi:10.1007/BF00925738. PMID 8350865. S2CID 22140722.
  11. Misawa H, Yamaguchi M (August 2000). "The gene of Ca2+-binding protein regucalcin is highly conserved in vertebrate species". International Journal of Molecular Medicine. 6 (2): 191–6. doi:10.3892/ijmm.6.2.191. PMID 10891565.
  12. Yamaguchi M, Yamamoto T (June 1978). "Purification of calcium binding substance from soluble fraction of normal rat liver". Chemical & Pharmaceutical Bulletin. 26 (6): 1915–8. doi:10.1248/cpb.26.1915. PMID 699201.
  13. Yamaguchi M, Sugii K (February 1981). "Properties of calcium-binding protein isolated from the soluble fraction of normal rat liver". Chemical & Pharmaceutical Bulletin. 29 (2): 567–70. doi:10.1248/cpb.29.567. PMID 7273253.
  14. Yamaguchi M, Mori S (January 1988). "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. doi:10.1248/cpb.36.321. PMID 2837338.
  15. 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.
  16. Fujita T, Uchida K, Maruyama N (April 1992). "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. doi:10.1016/0304-4165(92)90108-7. PMID 1581340.
  17. Fujita T, Shirasawa T, Uchida K, Maruyama N (October 1992). "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. doi:10.1016/0167-4781(92)90164-u. PMID 1420310.
  18. Shimokawa N, Yamaguchi M (August 1993). "Molecular cloning and sequencing of the cDNA coding for a calcium-binding protein regucalcin from rat liver". FEBS Letters. 327 (3): 251–5. doi:10.1016/0014-5793(93)80998-a. PMID 8348951. S2CID 1303220.
  19. Yamaguchi M, Makino R, Shimokawa N (December 1996). "The 5' end sequences and exon organization in rat regucalcin gene". Molecular and Cellular Biochemistry. 165 (2): 145–50. doi:10.1007/bf00229476. PMID 8979263. S2CID 10508949.
  20. Yamaguchi M (January 2011). "The transcriptional regulation of regucalcin gene expression". Molecular and Cellular Biochemistry. 346 (1–2): 147–71. doi:10.1007/s11010-010-0601-8. PMID 20936536. S2CID 22077914.
  21. Yamaguchi M (March 2005). "Role of regucalcin in maintaining cell homeostasis and function (review)". International Journal of Molecular Medicine. 15 (3): 371–89. doi:10.3892/ijmm.15.3.371. PMID 15702226.
  22. Yamaguchi M (August 2010). "Regucalcin and metabolic disorders: osteoporosis and hyperlipidemia are induced in regucalcin transgenic rats". Molecular and Cellular Biochemistry. 341 (1–2): 119–33. doi:10.1007/s11010-010-0443-4. PMID 20349117. S2CID 12577305.
  23. 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.
  24. Yamaguchi M, ed. (2019). Regucalcin: Metabolic Regulation and Disease. New York: Nova Science Publishers. pp. 1–176. ISBN 978-1536161724.
  25. Yamaguchi M (August 2015). "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. doi:10.1007/s00432-014-1831-z. PMID 25230901. S2CID 25371567.
  26. Yamaguchi M, Osuka S, Weitzmann MN, El-Rayes BF, Shoji M, Murata T (May 2016). "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. doi:10.3892/ijo.2016.3409. PMID 26935290.
  27. Cardosoa AL, Fernandes A, Aguilar-Pimentelc JA, de Angelisd MH, Guedes JR, Britob MA, Ortolano S, Pani G, Athanasopoulou S, Gonos ES, Schosserer M, Grillari J, Peterson P, Tuna BG, Dogan S, Meyer A, van Os R, Trendelenburg AU (July 2018). "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. doi:10.1016/j.arr.2018.07.004. PMID 30071357.
  28. Nitschkowski D, Marwitz S, Kotanidou SA, Reck M, Kugler C, Rabe KF, Ammerpohl O, Goldmann T (November 2019). "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. doi:10.1186/s13148-019-0770-6. PMC 6852724. PMID 31718698.

Further reading
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