Alternative titles; symbols
HGNC Approved Gene Symbol: REG1A
Cytogenetic location: 2p12 Genomic coordinates (GRCh38): 2:79,120,488-79,123,409 (from NCBI)
REG1A belongs to a family of secreted proteins containing a C-type lectin domain. It plays a role in proliferation, differentiation, and inflammation (Acquatella-Tran Van Ba et al., 2012).
Pancreatic stone protein is the major component of the protein matrix of calculi in patients with chronic calcifying pancreatitis. Secretory pancreatic stone protein (PSPS) is a glycoprotein in the pancreatic secretion that occurs in multiple molecular forms due to posttranslational processing. PSPS accounts for 10 to 14% of total protein in pancreatic juice, suggesting that it plays an important role in exocrine pancreatic function. Giorgi et al. (1989) isolated a cDNA encoding pre-PSPS from a human pancreas cDNA library. The deduced 166-amino acid protein has a calculated molecular mass of 18.7 kD. It has a 22-amino acid N-terminal prepeptide. The C-terminal domain of PSPS is similar to those of several serine proteases, and it includes the highly conserved ser-trp-gly tripeptide predicted to determine specificity of the substrate-binding pocket. Northern blot analysis of total pancreas RNA detected a 0.9-kb PSPS transcript.
Terazono et al. (1988) cloned and sequenced a cDNA derived from pancreatic islets following partial pancreatectomy. On the basis of its induction during regrowth of the pancreas and its apparent origin from islets, the corresponding gene was termed REG, with the implication that the gene was involved in islet regeneration. Stewart (1989) found that the sequence was identical to that of pancreatic stone protein.
Using Northern blot analysis, Watanabe et al. (1990) found robust expression of an approximately 0.9-kb REG1A transcript in human pancreas, with weaker expression in gastric mucosa and kidney. Expression was absent in other human tissue examined. Western blot analysis of human pancreas detected REG1A proteins with apparent molecular masses of 16 to 18 kD. Deglycosylation reduced the masses of the higher bands.
Using immunohistochemical analysis, de la Monte et al. (1990) found that PTP was expressed in fetal and infant brain. At 24 weeks' gestation, PTP immunoreactivity was faint, but it increased progressively as a function of age up to 6 months. PTP localized predominantly to neuropil, with intense staining of choroid plexus and ependymal cells lining the ventricular system. Minimal cerebral immunoreactivity was detected in a neurologically intact 16-year-old cystic fibrosis (219700) patient and in normal aged adult brain.
Unno et al. (1993) demonstrated a second Reg gene in the mouse and raised the possibility of a second REG gene in the human genome. Gharib et al. (1993) demonstrated that, in addition to the REG gene and the REG pseudogene in human, there is another sequence, which they named REGL (REG1B; 167771). Bartoli et al. (1993) found that the proteins encoded by REG and REG1B contain 166 amino acids and differ by only 22 amino acids.
Using probes that did not differentiate between REG1A and REG1B for in situ hybridization and immunohistochemical analysis, Sanchez et al. (2001) found that REG1A and/or REG1B were expressed in acinar cells of human fetal and adult pancreas. RT-PCR analysis using specific primers showed that both transcripts were more highly expressed in adult pancreas than in fetal pancreas. REG1A was the dominant species in fetal samples, and REG1B was the dominant species in adult samples. There did not appear to be developmental regulation of REG1A and REG1B expression between 16 and 41 weeks' gestation.
Using SDS-PAGE and Western blot analysis, Acquatella-Tran Van Ba et al. (2012) found that monomeric human and rodent Reg1a had apparent molecular masses ranging from 18 to 22 kD, likely due to variable O-glycosylation. Reg1a also formed dimers and tetramers with apparent molecular masses of about 35 and 70 kD, respectively. Immunofluorescence analysis of rat PC12 cells and cultured hippocampal neurons and mouse N2a cells detected Reg1a along perinuclear membranes and at growth cones.
The REG and REG-related genes constitute a multigene family. Based on the amino acid sequence homology among proteins encoded by REG genes, the members of the family can be grouped into 3 subclasses: type I, II, and III. Miyashita et al. (1995) stated that in the human 4 REG family genes had been isolated, which they designated REG I-alpha (REG1A), REG I-beta (REG1B), RS (REG-related sequence), and PAP (167805). REG1A and REG1B belong to the type I subclass and each gene encodes a 166-amino acid protein. RS shows a high degree of homology to REG1 genes but has an in-frame stop codon in the protein-coding region. PAP (also called HIP for 'gene expressed in hepatocellular carcinoma, intestine and pancreas') encodes a 175-amino acid protein exhibiting 49% amino acid identity with REG I proteins and belonging to the type III subclass.
Giorgi et al. (1989) determined that the REG1A gene contains at least 2 exons. The REG1A transcript has 2 canonical polyadenylation signals.
Watanabe et al. (1990) determined that the REG1A gene contains 6 exons and spans about 3 kb. Exon 1 is noncoding. The upstream region contains TATA and CCAAT boxes and an Alu element. REG1A has multiple transcription initiation sites.
Using in situ hybridization, Gharib et al. (1993) found that the REG and REGL genes both map to chromosome 2p12. Using PCR to study mouse/human and hamster/human hybrid cell lines, as well as fluorescence in situ hybridization, Perfetti et al. (1994) assigned the REG gene to chromosome 2p12.
By analyzing YAC clones containing the REG1A, REG1B, RS, and PAP genes and performing 2-color fluorescence in situ hybridization, Miyashita et al. (1995) demonstrated that these genes are tandemly ordered in a 95-kb DNA region of chromosome 2p12 as follows: 2cen--PAP--RS--REG1A--REG1B--pter.
Giorgi et al. (1989) noted that in vitro experiments have shown that PSPS inhibits CaCO(3) crystal growth. Since normal pancreatic secretions are supersaturated in CaCO(3), they proposed that the physiologic role of PSPS may be related to its inhibitory properties, a hypothesis supported by diminished PSPS concentration in pancreatic juice of patients with chronic calcifying pancreatitis. Giorgi et al. (1989) found that the PSPS mRNA level was 3 times lower in chronic calcifying pancreatitis patients than in controls. In contrast, the mRNA levels for trypsinogen, chymotrypsinogen, and colipase were not altered. Giorgi et al. (1989) concluded that PSPS gene expression is specifically reduced in patients with chronic calcifying pancreatitis.
De la Monte et al. (1990) found that PTP mRNA and protein were elevated in Alzheimer disease (AD; 104300) brain compared with normal aged controls. Expression in AD brain localized to pyramidal neurons in the cerebral cortex.
Verdier et al. (1992), who referred to pancreatic stone protein as lithostathine (Sarles et al., 1990), presented evidence that the kidney produces a protein immunologically similar to lithostathine. They suggested that it is responsible for preventing the formation of renal stones since the urine in the thin descending limb of the Henle loop is supersaturated in CaCO(3), as is pancreatic juice.
Cerini et al. (1999) stated that the secreted form of lithostathine had been found precipitated in fibrils in chronic calcifying pancreatitis and in Alzheimer disease. The 144-amino acid secreted form binds CaCO(3) crystals, altering its crystal habit in vitro. Cerini et al. (1999) showed that secreted lithostathine aggregated at physiologic pH and that formation of fibrils required proteolysis of an arg-ile bond, generating a 133-amino acid peptide.
Akiyama et al. (2001) studied the mechanism by which the REG gene is activated in beta cells. They found that the combined addition of interleukin-6 (IL6; 147620) and dexamethasone induced the expression of the REG gene in beta cells and that inhibitors of poly(ADP-ribose) polymerase (PARP; 173870) enhanced the expression. PARP inhibitors enhanced the DNA-protein complex formation for REG gene transcription and stabilized the complex by inhibiting the autopoly(ADP-ribosyl)ation of PARP.
Using cDNA representation difference analysis, Shinozaki et al. (2001) found that expression of REG1A was upregulated in inflamed colonic mucosa, including active ulcerative colitis (266600), Crohn disease (266600), and noninflammatory bowel disease lesions. In situ hybridization detected REG1A expression in crypt epithelial cells of affected tissue, but not in normal mesenchymal cells. In HT29 human colon cancer cells, REG1A was expressed during rapid cell growth, but it was downregulated when cells achieved confluence.
Using rat and mouse neurogenic cell lines and rat primary hippocampal cells, Acquatella-Tran Van Ba et al. (2012) found that expression of human REG1A or exposure to recombinant human REG1A in the culture medium lengthened neuronal extensions. Conversely, knockdown of Reg1a in PC12 or hippocampal neurons reduced the length of neurites. Antibody-dependent depletion of Reg1a or deletion of the signal sequence required for REG1A secretion also reduced neurite length. Cotransfection and knockdown studies revealed that Extl3 (605744) functioned as the Reg1a receptor in rodent neurons.
Yamaoka et al. (2000) found that mice engineered to overexpress Reg1 in pancreatic islet cells developed diabetes by apoptosis of beta cells. They also observed compensatory islet regeneration, proliferation of ductal epithelial cells, and development of various malignant tumors in these mice.
Acquatella-Tran Van Ba, I., Marchal, S., Francois, F., Silhol, M., Lleres, C., Michel, B., Benyamin, Y., Verdier, J.-M., Trousse, F., Marcilhac, A. Regenerating islet-derived 1-alpha (Reg-1-alpha) protein is new neuronal secreted factor that stimulates neurite outgrowth via exostosin tumor-like 3 (EXTL3) receptor. J. Biol. Chem. 287: 4726-4739, 2012. [PubMed: 22158612] [Full Text: https://doi.org/10.1074/jbc.M111.260349]
Akiyama, T., Takasawa, S., Nata, K., Kobayashi, S., Abe, M., Shervani, N. J., Ikeda, T., Nakagawa, K., Unno, M., Matsuno, S., Okamoto, H. Activation of Reg gene, a gene for insulin-producing beta-cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc. Nat. Acad. Sci. 98: 48-53, 2001. [PubMed: 11134536] [Full Text: https://doi.org/10.1073/pnas.98.1.48]
Bartoli, C., Gharib, B., Giorgi, D., Sansonetti, A., Dagorn, J.-C., Berge-Lefranc, J.-L. A gene homologous to the reg gene is expressed in human pancreas. FEBS Lett. 327: 289-293, 1993. [PubMed: 8348956] [Full Text: https://doi.org/10.1016/0014-5793(93)81006-l]
Cerini, C., Peyrot, V., Garnier, C., Duplan, L., Veesler, S., Le Caer, J.-P., Bernard, J.-P., Bouteille, H., Michel, R., Vazi, A., Dupuy, P., Michel, B., Berland, Y., Verdier, J.-M. Biophysical characterization of lithostathine: evidences for a polymeric structure at physiological pH and a proteolysis mechanism leading to the formation of fibrils. J. Biol. Chem. 274: 22266-22274, 1999. [PubMed: 10428794] [Full Text: https://doi.org/10.1074/jbc.274.32.22266]
de la Monte, S. M., Ozturk, M., Wands, J. R. Enhanced expression of an exocrine pancreatic protein in Alzheimer's disease and the developing human brain. J. Clin. Invest. 86: 1004-1013, 1990. [PubMed: 2394826] [Full Text: https://doi.org/10.1172/JCI114762]
Gharib, B., Fox, M. F., Bartoli, C., Giorgi, D., Sansonetti, A., Swallow, D. M., Dagorn, J. C., Berge-Lefranc, J. L. Human regeneration protein/lithostathine genes map to chromosome 2p12. Ann. Hum. Genet. 57: 9-16, 1993. [PubMed: 8333731] [Full Text: https://doi.org/10.1111/j.1469-1809.1993.tb00882.x]
Giorgi, D., Bernard, J.-P., Rouquier, S., Iovanna, J., Sarles, H., Dagorn, J.-C. Secretory pancreatic stone protein messenger RNA: nucleotide sequence and expression in chronic calcifying pancreatitis. J. Clin. Invest. 84: 100-106, 1989. [PubMed: 2525567] [Full Text: https://doi.org/10.1172/JCI114128]
Miyashita, H., Nakagawara, K., Mori, M., Narushima, Y., Noguchi, N., Moriizumi, S., Takasawa, S., Yonekura, H., Takeuchi, T., Okamoto, H. Human REG family genes are tandemly ordered in a 95-kilobase region of chromosome 2p12. FEBS Lett. 377: 429-433, 1995. [PubMed: 8549770] [Full Text: https://doi.org/10.1016/0014-5793(95)01381-4]
Perfetti, R., Hawkins, A. L., Griffin, C. A., Egan, J. M., Zenilman, M. E., Shuldiner, A. R. Assignment of the human pancreatic regenerating (REG) gene to chromosome 2p12. Genomics 20: 305-307, 1994. [PubMed: 8020983] [Full Text: https://doi.org/10.1006/geno.1994.1173]
Sanchez, D., Figarella, C., Marchand-Pinatel, S., Bruneau, N., Guy-Crotte, O. Preferential expression of Reg I-beta gene in human adult pancreas. Biochem. Biophys. Res. Commun. 284: 729-737, 2001. [PubMed: 11396963] [Full Text: https://doi.org/10.1006/bbrc.2001.5033]
Sarles, H., Dagorn, J. C., Giorgi, D., Bernard, J. P. Renaming pancreatic stone protein as 'lithostathine'. (Letter) Gastroenterology 99: 900-901, 1990. [PubMed: 2379794] [Full Text: https://doi.org/10.1016/0016-5085(90)90999-h]
Shinozaki, S., Nakamura, T., Iimura, M., Kato, Y., Iizuka, B., Kobayashi, M., Hayashi, N. Upregulation of Reg 1-alpha and GW112 in the epithelium of inflamed colonic mucosa. Gut 48: 623-629, 2001. [PubMed: 11302958] [Full Text: https://doi.org/10.1136/gut.48.5.623]
Stewart, T. A. The human REG gene encodes pancreatic stone protein. (Letter) Biochem. J. 260: 622-623, 1989. [PubMed: 2764894] [Full Text: https://doi.org/10.1042/bj2600622]
Terazono, K., Yamamoto, H., Takasawa, S., Shiga, K., Yonemura, Y., Tochino, Y., Okamoto, H. A novel gene activated in regenerating islets. J. Biol. Chem. 263: 2111-2114, 1988. [PubMed: 2963000]
Unno, M., Yonekura, H., Nakagawara, K., Watanabe, T., Miyashita, H., Moriizumi, S., Okamoto, H. Structure, chromosomal localization, and expression of mouse reg genes, reg I and reg II: a novel type of reg gene, reg II, exists in the mouse genome. J. Biol. Chem. 268: 15974-15982, 1993. [PubMed: 8340418]
Verdier, J. M., Dussol, B., Casanova, P., Daudon, M., Dupuy, P., Berthezene, P., Boistelle, R., Berland, Y., Dagorn, J. C. Evidence that human kidney produces a protein similar to lithostathine, the pancreatic inhibitor of CaCO(3) crystal growth. Europ. J. Clin. Invest. 22: 469-474, 1992. [PubMed: 1516594] [Full Text: https://doi.org/10.1111/j.1365-2362.1992.tb01492.x]
Watanabe, T., Yonekura, H., Terazano, K., Yamamoto, H., Okamoto, H. Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues: the reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. J. Biol. Chem. 265: 7432-7439, 1990. [PubMed: 2332435]
Yamaoka, T., Yoshino, K., Yamada, T., Idehara, C., Hoque, M. O., Moritani, M., Yoshimoto, K., Hata, J., Itakura, M. Diabetes and tumor formation in transgenic mice expressing Reg I. Biochem. Biophys. Res. Commun. 278: 368-376, 2000. [PubMed: 11097844] [Full Text: https://doi.org/10.1006/bbrc.2000.3813]