ISSN: 2168-9652
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Regucalcin may be a Key Molecule in Cell Nuclear Regulation

Masayoshi Yamaguchi*
Department of Hematology and Biomedical Oncology, Emory University School of Medicine, Atlanta, USA
*Corresponding Author : Masayoshi Yamaguchi
Department of Hematology and Biomedical Oncology
Emory University School of Medicine, 1365 C Clifton Road
NE, Atlanta, GA 30322, USA
Tel: 404-664-7422
E-mail: yamamasa1155@yahoo.co.jp
Received July 18, 2013; Accepted July 18, 2013; Published July 22, 2013
Citation: Yamaguchi M (2013) Regucalcin may be a Key Molecule in Cell Nuclear Regulation. Biochem Physiol 2:e116. doi:10.4172/2168-9652.1000e116
Copyright: © 2013 Yamaguchi M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Regucalcin was discovered in 1978 as a Ca2+-binding protein that contains no EF-hand motif of Ca2+-binding domain [1-4]. The regucalcin gene is localized on X chromosome [5,6], and the organization of regucalcin gene consists of seven exons and six introns [7]. Regucalcin (RGN) and its gene (rgn) are identified in over 15 species consisting of regucalcin family in vertebrate and invertebrate species [4,8,9]. Various transcription factors have been shown to enhance transcription activity of the regucalcin gene expression that is mediated through Ca2+ and other signal systems [9]. Regucalcin plays a multifunctional role in cell regulation; maintaining of intracellular Ca2+ homeostasis, suppressions of signal transduction, protein synthesis, cell proliferation and apoptosis [10,11]. Regucalcin has been proposed to play an important role in maintaining cell homeostasis [11]. Moreover, regucalcin has been shown to involve in various pathophysiologic states [12]. Interestingly, regucalcin, which is present in the cytoplasm, is translocated into the nucleus of various cell types, and it plays a pivotal role in the regulation of nuclear function.
Nuclear translocation of regucalcin is not regulated through adenosine 5’-triphosphate and guanosine 5’-triphosphate, which are required for nuclear import of proteins [13]. Moreover, this translocation is not changed with the lectin wheat germ agglutinin, which suppresses transport of nuclear protein [14]. Nuclear translocation of regucalcin is not related to nuclear localization signal that is responsible for selection for intranuclear active transport. Regucalcin may be passively transported to the nucleus through nuclear pore in cells, since the molecular weight of regucalcin is about 33 kDa [4]. Regucalcin has also been shown to localize in the nuclei of the cloned normal rat kidney proximal tubular epithelial NRK52E cells with immunocytochemical analysis [15]. Nuclear localization of regucalcin is enhanced through hormonal Ca2+-signaling dependent process that is involved protein kinase C [15]. Regucalcin has been shown to bind protein and DNA in the nucleus [16]. Regucalcin has been shown to regulate various enzyme activities in the nucleus. Endonuclease is responsible for DNA fragmentation occurring during programmed cell death (apoptosis) and certain forms of chemically induced cell killing [17]. Regucalcin has been found to have suppressive effects on Ca2+-activated DNA fragmentation due to inhibiting endonuclease activity in isolated rat liver nuclei [18]. Smal GTPase Ran (ras-related nuclear protein) is required for protein export from the nucleus and protein import into the nucleus [19]. Regucalcin inhibits GTPase activity in rat liver nucleus [13]. Process of signal transduction from the cytoplasm to nucleus in liver cells is mediated through various protein kinases and protein phosphatases. Regucalcin is found to suppress the activities of tyrosine kinase, protein kinase C and Ca2+/calmodulin-dependent protein kinase, which are enhanced in the cytoplasm and nucleus obtained from regenerating rat liver with proliferating cells in vivo [20]. The activity of nuclear Ca2+-dependent protein kinases has been shown to increase in the presence of anti-regucalcin monoclonal antibody in the enzyme reaction mixture, and such increases are completely depressed with addition of regucalcin [20]. In addition, nuclear endogenous regucalcin has been shown to play a suppressive role in the regulation of protein tyrosine phosphatases using anti-regucalcin monoclonal antibody in the reaction mixture [21]. Thus, regucalcin has been shown to play a pivotal role in the regulation of the activity of various enzymes in the nucleus.
Regucalcin has also been shown to have suppressive effects on DNA and RNA synthesis activity in the nuclei of normal rat liver and regenerating rat liver in vivo [22-25]. Regucalcin may have suppressive effects on the enhancement of nuclear DNA and RNA synthesis in proliferating liver cells in vivo. Also, regucalcin has a suppressive effect on DNA synthesis activity in the nuclei isolated from rat renal cortex in vitro [26]. The presence of anti-regucalcin monoclonal antibody in the reaction mixture causes an increase in nuclear DNA synthesis activity [22,23]. This increase was completely depressed in the presence of regucalcin. Thus, endogenous regucalcin is found to have a suppressive effect on DNA synthesis in the nuclei of rat liver and renal cortex [22,23]. The effect of regucalcin in decreasing nuclear RNA synthesis activity in normal rat liver is not seen in the presence of α-amanitin, an inhibitor of RNA polymerase II and III [24,25], suggesting that its suppressive effect is partly resulted from the inhibitory action on RNA polymerase II and III. Regucalcin may have direct inhibitory effects on nuclar DNA and RNA polymerase activity. Moreover, regucalcin has been shown to regulate nuclear function in proliferating cells using cloned hepatoma H4-II-E cells which were cultured in the presence of fetal bovine serum (FBS). Culture with FBS produced an increase in cell number and a corresponding elevation of various kinase activities, which are related to Ca2+/calmodulin-dependent protein kinase, protein kinase C, protein tyrosine kinase and protein phosphatase activity in H4-II-E cells [27-29]. These enzymes may contribute to the enhancement of hepatoma cell proliferation after serum stimulation. The presence of anti-regucalcin monoclonal antibody in the enzyme reaction mixture using H4-II-E cells cultured with FBS stimulation was found to increase the activities of protein kinase and protein phosphatase. Such an effect was depressed after addition of exogenous regucalcin in the enzyme reaction mixture. Regucalcin may play an important role as a suppressor in the enhancement of cell proliferation due to inhibiting the activities of various protein kinases and protein phosphatases in the cytoplasm and nucleus [27-29]. In addition, nuclear DNA synthesis activity has been shown to increase at 6 hours after culture with FBS, which is preceded an elevation of the number of H4-II-E cells cultured with FBS [30,31]. The presence of regucalcin in the reaction mixture suppressed nuclear DNA synthesis activity in the cells. This effect may be partly mediated through pathway of various protein kinases in H4-II-E cells. Endogenous regucalcin has been shown to suppress DNA synthesis activity through mechanism by which inhibits protein kinases in the nuclei of proliferating H4-II-E cells using anti-regucalcin monoclonal antibody [30]. To determine the role of endogenous regucalcin in the regulation of nuclear DNA synthesis, regucalcin/ pCXN2-transfected cells, which H4-II-E cells overexpress regucalcin stably, have been generated [31]. The increase in cell number and DNA synthesis activity in transfectants was found to suppress as compared with those of wild- and mock-type, indicating that overexpression of endogenous regucalcin has suppressive effects on cell proliferation [31]. The presence of anti-regucalcin monoclonal antibody in the reaction mixture caused increases in DNA synthesis activity in the nuclei obtained from wild-type H4-II-E cells, mock-type cells, and transfectants with overexpression of regucalcin [31]. However, such an increase was remarkable in transfectants [31]. This finding supports the view that the augmentation of endogenous regucalcin has great suppressive effects on nuclear DNA synthesis activity in proliferating hepatoma cells. Regucalcin may play a suppressive role for the overproliferation of liver cells.
Whether regucalcin suppresses cell cycle-realted genes in proliferating cells has been examined. Overexpression of regucalcin is found to induce G1 and G2/M phase cell cycle arrest in transfectants (H4-II-E cells) [32]. p21 mRNA expression was found to enhance in transfectants, although cdc2a and chk2 (checkpoint-kinase 2) mRNA levels were not changed [32]. p21 is an inhibitor of cyclin-dependent kinases (cdk). Regucalcin may enhance p21 expression and inhibits G1 progression in H4-II-E cells. Overexpression of endogenous regucalcin has also been shown to suppress proliferation of cloned normal rat kidney proximal tubular epithelial NRK52E cells [33]. Endogenous regucalcin is found to induce G1 and G2/M phase cell cycle arrest in NRK52E cells [33]. Expression of c-jun and chk2 (checkpoint-kinase 2) mRNAs was also suppressed in the transfectants of NRK52E cells [33]. The expression of c-myc, c-fos, cdc2, and p21mRNAs was not changed in transfectants [33]. Decrease in c-jun and chk2 mRNA expressions may partly contribute to suppression of cell proliferation induced in regucalcin-overexpressing NRK52E cells. c-myc, c-fos, c-jun, and Haras are known as tumor stimulator genes [34]. p53 and Rb are tumor suppressor genes, and c-src is oncogene [35]. Expression of c-myc, Haras, or c-src mRNAs was found to suppresse in regucalcin-overexpressing transfectants [36]. Expression of p53 and Rb mRNAs was markedly enhanced in transfectants [36]. Suppressed expression of c-myc, Ha-ras and c-src mRNAs and enhanced expression of p53 and Rb mRNAs in transfectants may be partly involved in retardation of proliferation of hepatoma H4-II-E cells. Also, expression of p53 mRNA was enhanced in regucalcin-overespressing transfectants of NRK52E cells, while expression of c-myc, c-fos, cdc2, and p21mRNAs was not changed in transfectants [33]. Decrease in c-jun and chk2 mRNA expressions may partly contribute to suppression of cell proliferation induced in NRK52E cells overexpressing regucalcin. p53 mRNA expression, which was enhanced in transfectants, may play a role in retardation of proliferation of NRK52E cells. Thus, regucalcin has been shown to have suppressive effects on cell proliferation due to regulating many gene expressions that are related to cell proliferation in hepatoma H4-II-E cells and normal kidney NRK52E cells. Regucalcin can bind DNA and modulates nuclear transcriptional activity [16]. Regucalcin may bind to the promoter region of various genes which suppress stimulator gene expression or stimulate suppressor gene expression in cell proliferation. As the result, overexpression of endogenous regucalcin suppresses cell proliferation. Regucalcin may play an important role as a suppressor protein in cell proliferation.
Regucalcin has been shown to regulate gene expression of proteins which are related to apoptosis. Overexpression of regucalcin has a suppressive effect on apoptotic cell death induced by tumor necrosis factor (TNF)-α, lypopolyssacharide, Bay K 8644, or thapsigargin in NRK52E cells, suggesting that its suppressive effects may be mediated through many intracellular signaling pathways in NRK52E cells. Bcl-2 is a suppressor protein in apoptotic cell death [37]. Apaf-1 participates in activation of caspase-3 [38]. Akt-1 is involved in survival signaling pathway for cell death [39]. Overexpression of regucalcin caused a remarkable elevation of Bcl-2 mRNA expression in NRK52E cells, and it slightly stimulated Akt-1 mRNA expression in the cells. The expression of Apaf-1 or caspase-3 mRNAs was not changed in transfectants [37]. The enhancement of Bcl-2 mRNA expression may contribute to suppression of apoptotic cell death in NRK52E cells. Regucalcin may play a role in the regulation of Bcl-2 gene expression in NRK52E cells. Regucalcin regulates the expression of Bcl-2, caspase-3, and Akt-1 mRNAs in NRK52E cells. Thus, regucalcin rescues apoptosis that is mediated through gene expression of protein molecule which is related to cell apoptosis. Interestingly, overexpression of regucalcin has been found to have suppressive effects on the remarkable increase in α-smooth muscle actin level in NRK52E cells cultured with TNF-α or transforming growth factor (TGF)-β1 [40]. This finding suggests that regucalcin regulates signal pathway that is mediated through TNF-α or TGF-β1 to stimulate α-smooth muscle actin expression. TGF-β1 is a key mediator that regulates transdifferentiation of NRK52E cells into myofibroblasts due to expressing α-smooth muscle actin which is contributed to renal fibrosis associated with overexpression of TGF-β1 within diseased kidney [41]. Regucalcin may regulate transdifferentiation to renal fibrosis in NRK52E cells with TGF-β1 or TNF-α. In addition, overexpression of regucalcin caused a remarkable increase in Smad 2 mRNA expression, which is involved in signal transduction of TGF-β1 [41], and NF-κB mRNA expression, which is related to signal of TNF-α [42], in NRK52E cells. Regucalcin may have suppressive effects on signal pathway by which TNF-α or TGF-β1 stimulates gene expression of NF-κB or Smad 2 in NRK52E cells. In addition, regucalcin has been shown to regulate the gene expressions of other proteins. Overexpression of regucalcin increases glucose transporter 2 mRNA expression [43] and it suppresses rat insulin receptor (Insr) or phosphatidylinositol 3-kinase (PI3K) mRNAs expression in H4-II-E cells, which are related to insulin signaling [44]. Regucalcin has also been shown to have suppressive effects on the gene expression of L-type Ca2+ channel and Ca2+-sensing receptor (CaR), which regulate calcium transport system in NRK52E cells, and it causes an increase in rat outer medullary K+channel (ROMK) mRNA expression in the cells [45], suugesting a role of regucalcin in the regulation of mineral ion transports in the kidney proximal tubular epithelial cells. Thus, regucalcin has been proposed to have a role as a transcriptional factor in the nucleus.
As described above, regucalcin has been shown to translocate into the nucleus of various cell types. Regucalcin binds nuclear proteins and DNA, and it suppresses DNA and RNA synthesis and the phosphorylation and dephosphorylation of various proteins which are related to transcription. In addition, regucalcin may directly bind on the promoter region of gene and regulates the expression of various genes as a transcription factor. Regucalcin may be a key molecule in cell nuclear regulation. Further studies will be expected.
Acknowledgements
Regucalcin studies of the author was supported by a Grant-in-Aid for Scientific Research (C) No.63571053, No.02671006, No.04671362, No.06672193, No.08672522, No.10672048, No.13672292 and No.17590063 from the Ministry of Education, Science, Sports, and Culture, Japan. Also, the author was awarded the Bounty of Encouragement Foundation in Pharmaceutical Research and the Bounty of the Yamanouchi Foundation for Research on Metabolic Disorders. This study was also supported by the Fundation for Biomedical Research on Regucalcin.
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