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PubMed1984

The molecular characteristics of a human pancreatic acidic phosphoprotein that inhibits calcium carbonate crystal growth.

A CaCO3-crystal-growth inhibitor was isolated from human pancreatic stones by using EDTA demineralization, followed by DEAE-Trisacryl chromatography. The isolated inhibitor was found to be a phosphoglycoprotein with Mr 14017 and having an unusual chemical composition. It is characterized by a high (42%) acidic amino acid content, but lacks methionine and gamma-carboxyglutamic acid. The protein contains 2.65 mol of P/mol of protein, as phosphoserine (2 mol) and phosphothreonine (0.5 mol). Isoelectric focusing of the protein yields one major band corresponding to an isoelectric point of 4.2. Immunochemical quantification of the crystal-growth inhibitor in pure pancreatic juice reveals that it constitutes 14% of the normal exocrine secretion. Our findings demonstrate that this is a novel secretory protein, which has no enzymic activity and which maintains pancreatic juice in a supersaturated state with respect to CaCO3.

Amino Acids↗
PubMed1986

Partial amino acid sequence of human pancreatic stone protein, a novel pancreatic secretory protein.

Pancreatic stone protein (PSP) is the major organic component of human pancreatic stones. With the use of monoclonal antibody immunoadsorbents, five immunoreactive forms (PSP-S) with close Mr values (14,000-19,000) were isolated from normal pancreatic juice. By CM-Trisacryl M chromatography the lowest-Mr form (PSP-S1) was separated from the others and some of its molecular characteristics were investigated. The Mr of the PSP-S1 polypeptide chain calculated from the amino acid composition was about 16,100. The N-terminal sequences (40 residues) of PSP and PSP-S1 are identical, which suggests that the peptide backbone is the same for both of these polypeptides. The PSP-S1 sequence was determined up to residue 65 and was found to be different from all other known protein sequences.

Amino Acid Sequence↗
PubMed1995

Ethanol inhibits insulin receptor substrate-1 tyrosine phosphorylation and insulin-stimulated neuronal thread protein gene expression.

Neuronal thread proteins (NTPs) are molecules that accumulate in the brains of patients with Alzheimer's disease, and may play a key role in both normal and neurodegenerative neuritic sprouting. In this investigation we determined whether NTP expression is up-regulated by insulin, an important neurotrophic factor that stimulates differentiation-associated neurite outgrowth, and studied the effects of ethanol, a known inhibitor of growth factor receptor tyrosine phosphorylation, on NTP expression and insulin-mediated signal transduction cascade in neuronal [primitive neuroectodermal tumour cell line 2; (PNET2)] cells. PNET2 cells were treated with 50 m-units/ml insulin in the presence or absence of 100 mM ethanol for 0.2-96 h, and cell proliferation and expression of NTP molecules were investigated by metabolic labelling, immunoprecipitation and immunohistochemical staining. Insulin stimulation resulted in an immediate increase in the levels of three (38, 18 and 15 kDa) of five NTP species (the others were of 26 and 21 kDa), followed by a decline in expression within 120 min; however, studies performed up to 96 h of culture demonstrated up-regulation by insulin of all five NTP species. Ethanol either abolished or severely muted the short- and long-term insulin-mediated upregulation of NTP expression, and substantially reduced insulin-mediated neuronal differentiation. The effects of ethanol on NTP gene expression were associated with impaired insulin-mediated tyrosine phosphorylation of both the insulin receptor beta subunit and the insulin receptor substrate-1 (IRS-1), resulting in decreased association of phosphatidylinositol 3-kinase with IRS-1. The findings suggest that ethanol may inhibit NTP expression associated with central nervous system neuronal differentiation by uncoupling the IRS-1-mediated insulin signal transduction pathway.

Calcium-Binding Proteins↗
PubMed1996

Pancreatic thread protein is mitogenic to pancreatic-derived cells in culture.

BACKGROUND & AIMS: Pancreatic thread proteins (PTPs) are acinar cell products and members of the regenerating gene (reg) family. reg expression increases during islet regeneration, is depressed during aging-related islet dysfunction, and may be important in beta-cell growth and maintenance. The aim of this study was to examine the genetic expression of reg in pancreatic-derived cells in vitro and the mitogenic effect of PTP/reg protein on these cells. METHODS: reg gene expression was measured by Northern analysis in three rat pancreatic cell lines: ARIP (ductal), AR42J (acinar), and RIN (beta-cell). PTP/reg protein was isolated from bovine and human pancreas. Cells were cultured with PTP/reg for 72 hours, and thymidine incorporation was measured. RESULTS: reg messenger RNA was detected in AR42J but not in ARIP or RIN. PTP/reg protein was mitogenic to RIN and ARIP in a dose-related fashion but not to AR42J. It was not mitogenic to cultured mature rat islets. CONCLUSIONS: reg messenger RNA is expressed in acinar but not in beta-cell or ductal pancreatic cell lines. PTP/reg protein was mitogenic to both beta-cell and ductal cell lines but not to mature, nondividing islets. This supports the hypothesis that PTP/reg protein is an acinar cell-derived mediator of beta-cell growth and may be involved in modulating the duct-to-islet axis.

Animals↗
PubMed1996

Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress.

BACKGROUND & AIMS: Reg gene has been isolated from regenerating rat pancreatic islets, and subsequent studies have shown a trophic effect of Reg protein on islet cells. However, little is known about the role of Reg protein in the stomach. The aim of this study was to clarify the localization of Reg messenger RNA (mRNA) and its product in the stomach and to examine changes in the level of their expression during regeneration of gastric mucosal cells. METHODS: Gastric lesions were experimentally induced in Sprague-Dawley rats by water immersion stress. Northern blot analysis and in situ hybridization studies were performed to examine changes in mRNA levels. Immunohistochemical studies were performed to identify the cellular localization and to investigate the change in Reg protein level. RESULTS: Reg mRNA and its product were distributed in the basal part of the oxyntic mucosa and were expressed mainly in enterochromaffin-like cells. Levels of both Reg mRNA and its product were markedly increased in the water immersion-induced gastric lesions. CONCLUSIONS: Reg mRNA and its product are expressed in gastric enterochromaffin-like cells, and their levels are increased during the healing process of water immersion-induced gastric lesions.

Animals↗
PubMed2000

Neutrophil chemoattractant 2 beta regulates expression of the Reg gene in injured gastric mucosa in rats.

BACKGROUND & AIMS: Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage. METHODS: Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation-enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2 beta). RESULTS: During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2 beta is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2 beta neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2 beta dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells. CONCLUSIONS: CINC-2 beta, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.

Animals↗
PubMed2004

Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130.

BACKGROUND AND AIMS: We have developed a mouse model of gastric cancer that resembles human intestinal-type adenocarcinoma. The aim of this study was to determine the identity and temporal changes in mediators of IL-6 signaling regulating tumor development. METHODS: gp130(757F/F) Mice that lack the SHP2-binding site on the IL-6 family receptor gp130 and have increased STAT 3 activity and wild-type littermates were used. Cohorts were assessed by quantitative histology and immunohistochemistry for gastric cell phenotype and proliferation markers from 4 to 40 weeks of tumor development. Northern blotting and in situ hybridization were used to quantify expression of the tumor suppressor TFF1 and the mitogens gastrin and Reg I. Expression of epidermal growth factor receptor (EGFr) and its ligands was measured by RT-PCR analysis. Age-matched differences in gene expression profiles were tested by ANOVA. RESULTS: Hyperplastic antral tumors with inflammation and ulceration were evident in gp130(757F/F) mice at 4 weeks of age and reached maximum size by 20 weeks. Tumor progression was marked by gastritis, atrophy, intestinal metaplasia, dysplasia, and submucosal invasion after 30 weeks. Both TFF1 and gastrin expression were progressively inhibited during tumorigenesis, whereas Reg I was stimulated. The EGFr and its ligands transforming growth factor (TGF)-alpha and heparin-binding EGF had increased expression corresponding to maximal tumor growth. CONCLUSIONS: gp130(757F/F) Mice rapidly develop distal stomach tumors, with loss of SHP2/Erk/AP-1 transcriptional regulation exemplified by decreased TFF1 expression and increased STAT1/3 regulated genes such as Reg I. Tumor development occurs in a hypogastrinemic environment. Balanced IL-6 signaling is required for maintaining gastric homeostasis.

Adenoma↗
PubMed2005

REG Ialpha protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer.

BACKGROUND & AIMS: Although a significant amount of regenerating gene (REG) Ialpha protein is present not only in normal gastric mucosa but also in gastric cancer tissues, its pathophysiologic role in gastric cancer development remains unclear. We investigated REG Ialpha protein expression in early gastric cancers, and examined whether cytokines are responsible for REG Ialpha gene expression and whether REG Ialpha protein has a trophic and/or an antiapoptotic effect on gastric cancer cells. METHODS: Early gastric cancer specimens were analyzed histologically using immunohistochemistry for REG Ialpha protein and proliferating cell nuclear antigen (PCNA). The effects of cytokines on REG Ialpha promoter activity and its messenger RNA (mRNA) expression in AGS (a kind of gastric cancer cell line) cells were examined by luciferase reporter assay and Northern blot analysis, respectively. Effects of REG Ialpha protein on cell growth and H2O2-induced apoptosis in AGS cells were examined by 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling (TUNEL) assays, respectively. RESULTS: REG Ialpha-positive early gastric cancers showed a significantly higher PCNA labeling index and more severe inflammatory cell infiltration in adjacent gastric mucosa than the negative cancers. REG Ialpha gene expression and its promoter activity were enhanced by interferon (IFN)-gamma and interleukin (IL)-6. REG Ialpha protein promoted cell growth and cell resistance to H2O2-induced apoptosis in AGS cells. These effects were abolished by concomitant treatment with anti-REG Ialpha antibody. REG Ialpha protein enhanced Akt phosphorylation and Bcl-xL expression in AGS cells. CONCLUSIONS: REG Ialpha gene is inducible by cytokine stimulation and its gene product may function as a mitogenic and/or an antiapoptotic factor in the development of early gastric cancer.

Apoptosis↗
PubMed2000

Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family.

An intrinsic component of colorectal carcinogenesis may be the capacity to activate regenerative responses simultaneously with inhibition of apoptosis. Since apoptosis is known to be inhibited in colorectal cancer, this study sought evidence for the activation of the REG family of genes which are considered to be activated during regeneration of intestinal mucosa. Transcripts for the REG gene were found in 53% of colorectal cancers and for the PAP gene in 60% of colorectal cancers, by RT-PCR. Using in situ hybridization, the REG transcripts were found to be present in the tumour cells themselves rather than inflammatory or stromal cells. There were no significant correlations between the expression of these two genes and tumour stage, age or sex of the patient population or tumour site. However, in patients with non-metastatic disease who underwent ostensibly curative surgery, the expression of REG alone and co-expression of REG with PAP had a highly significantly adverse effect on survival. These data provide support for the concept that, in some tumours, carcinogenesis involves a regenerative process which co-exists with apoptotic inhibition and may provide a valuable selective indicator of the need for adjuvant therapy in those patients with early-stage colorectal cancer whose disease is destined to recur after curative surgery.

ADP-Ribosylation Factors↗
PubMed2002

Localization of Reg receptor in rat fundic mucosa.

Reg protein has a trophic effect on gastric mucosal cells and pancreatic islets. Recently, the Reg receptor (Reg-R) has been cloned, and Reg-Reg-R interaction has been reported in the pancreas. The aim of this study was to investigate the localization of Reg-R in rat fundic mucosa. Gene expression of Reg-R was investigated with Northern blot analysis, laser capture microdissection coupled with reverse transcription-polymerase chain reaction, and in situ hybridization in the fundic mucosa, and the types of cells expressing this gene were determined. Reg-R mRNA expression was detected mainly in chief cells and parietal cells of the deep layers and faintly in surface epithelial cells and mucous neck cells of the proliferating zone. Our results suggest that regenerating protein may act not only as a regulator of gastric epithelial cell proliferation but also as a modifier of other multiple physiologic functions.

Animals↗
PubMed2005

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice.

In multiple systems, impaired proteolysis associated with the loss of the hemostatic factor plasminogen (Plg) results in fibrin-dependent defects in tissue repair. However, repair within the liver is known to be defective in Plg-deficient (Plg(o)) mice independent of fibrin clearance and appears to be compromised in part by the poor clearance of necrotic cells. Based on these findings, we examined the hepatic transcriptome after injury in search of transcriptional programs that are sensitive to the Plg/fibrinogen system. To this end, we generated biotinylated cRNA pools from livers of Plg(o) mice and controls before and after a single dose of the hepatotoxin carbon tetrachloride and hybridized them against high-density oligonucleotide arrays. Analysis of the gene expression platform identified an unexpected transcriptional signature within challenged livers of Plg(o) mice for pancreatic gene products, including trypsinogen-2, amylase-2, elastase-1, elastase-2, and cholesteryl-ester lipase. Validation studies found that this transcriptional program also contained products of the endocrine pancreas (Reg-1 and insulin genes) and the expression of the pancreatic transcription factors p48 and PDX-1. By using a LacZ transgene to trace the cellular source of pancreatic gene expression, we found that PDX-1 was expressed in albumin-positive cells that were morphologically indistinguishable from hepatocytes, and in albumin-negative epithelioid cells within zones of pericentral injury. More detailed studies revealed that the mechanisms of heterotopic gene expression in Plg(o) mice required fibrin(ogen). Collectively, these data reveal a regulatory role for the hemostatic factors plasmin(ogen) and fibrin(ogen) in cellular plasticity within adult tissues of the digestive system.

Amylases↗
PubMed1985

An unusual bovine pancreatic protein exhibiting pH-dependent globule-fibril transformation and unique amino acid sequence.

An unusual hitherto unreported protein, extracted in acid from fresh bovine pancreas, has been purified and characterized biochemically. It precipitates in the neutral pH range in the form of uniform double-helical threads, each strand of which is smooth and of uniform diameter, about 7-8 nm. The threads dissolve to a nonviscous solution below pH 3.6 and above pH 9.4, and they reconstitute reversibly in the pH range in between. The monomer in acid has an apparent molecular weight of 17,800 and consists of two disulfide-linked nonidentical polypeptide chains of different lengths. It is rich in aromatic amino acids, particularly tryptophan. There is no significant content of carbohydrate, fatty acid, or bound phosphate. The amino acid sequences of the first NH2-terminal 48 residues of the A chain and 35 residues of the B chain appear to be unique, differing from all other reported animal proteins, including those of the pancreas. Thus far, a function has not been found.

Amino Acid Sequence↗
PubMed1989

Elevated levels of an exocrine pancreatic secretory protein in Alzheimer disease brain.

We identified by a monoclonal antibody-based immunoradiometric assay high concentrations of an exocrine pancreatic protein called pancreatic thread protein (PTP) in several areas of Alzheimer disease (AD) brain. The saline-extractable soluble immunoreactivity shares at least three epitopes in common with the native pancreatic form of the protein; the Mr varies from approximately 17,000 to 20,000. Quantitative measurements of PTP immunoreactivity in various regions of several AD brains revealed levels varying from 12 to 295 ng/g of tissue (mean, 116 ng/g) compared with 1-11 ng/g of tissue (mean, 5 ng/g) found in comparable areas of control brains. Immunocytochemistry performed with the anti-PTP monoclonal antibodies demonstrate PTP immunoreactivity within large pyramidal neurons--many of which contain neurofibrillary tangles in both AD and Down syndrome. Less accumulation was observed in astrocytes, and some PTP immunoreactivity was found extracellularly. The highest number of labeled cells in AD and Down syndrome was seen in the hippocampal formation. Fewer positive-staining cells were noted in normal and disease control brains. We conclude, therefore, that an exocrine pancreatic protein is present in the central nervous system of normal individuals at low levels; in AD brain concentrations of this protein are much higher.

Alzheimer Disease↗
PubMed1994

Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein.

We previously isolated from a rat regenerating islet cDNA library a gene named Reg, which is expressed in regenerating islets but is not expressed in normal islets. Here we examined the effect of rat Reg protein on pancreatic beta-cell replication using both 90% depancreatized rats and isolated islets. The depancreatized rats that received i.p. administration of recombinant rat Reg protein (1 mg/kg per day) for 2 months showed amelioration of the surgical diabetes, as evidenced by a significant decrease in blood glucose with an increased beta-cell mass in the residual pancreas. In isolated rat islets, Reg protein (18-180 nM: 0.3-3 micrograms/ml) significantly increased [3H]thymidine incorporation into the nuclei of beta cells. These results indicate that Reg protein is a growth factor for pancreatic beta cells and also suggest that the administration of Reg protein could be used as another therapeutic approach for diabetes mellitus.

Animals↗
PubMed2001

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.

The regeneration of pancreatic islet beta cells is important for the prevention and cure of diabetes mellitus. We have demonstrated that the administration of poly(ADP-ribose) synthetase/polymerase (PARP) inhibitors such as nicotinamide to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library, we have isolated Reg (regenerating gene) and demonstrated that Reg protein induces beta-cell replication via the Reg receptor and ameliorates experimental diabetes. However, the mechanism by which Reg gene is activated in beta cells has been elusive. In this study, we found that the combined addition of IL-6 and dexamethasone induced the expression of Reg gene in beta cells and that PARP inhibitors enhanced the expression. Reporter gene assays revealed that the -81 approximately -70 region (TGCCCCTCCCAT) of the Reg gene promoter is a cis-element for the expression of Reg gene. Gel mobility shift assays showed that the active transcriptional DNA/protein complex was formed by the stimulation with IL-6 and dexamethasone. Surprisingly, PARP bound to the cis-element and was involved in the active transcriptional DNA/protein complex. The DNA/protein complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance the DNA/protein complex formation for Reg gene transcription and stabilize the complex by inhibiting the autopoly(ADP-ribosyl)ation of PARP.

Animals↗