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. Author manuscript; available in PMC: 2011 Jun 15.
Published in final edited form as: Einstein Q J Biol Med. 2000;17(4):178.

A Brief History of Pancreatic Reg: Implications as to its Clinical Importance

Haiyan Wu 1, Qinghu Zheng 1, Padmanabha Rengabhashyam 1, Michael E Zenilman 1
PMCID: PMC3115621  NIHMSID: NIHMS109904  PMID: 21687811

Abstract

Although the pancreatic regenerating (reg) gene, was first isolated from a rat regenerating islets in 1988, its protein product was originally described in the 1970s. Reg proteins arise from a multigene family with three subtypes, and have a protein structure similar to calcium dependent lectins. Reg I and II have been implicated in control of pancreatic development and may play a role in maintenance of the beta-cell mass in the mature pancreas. Administration of reg I protein has been used in experimental animals as a therapy for surgically-induced diabetes mellitus. Reg I protein is also an inhibitor of calcium carbonate crystalization, important in maintaining the fluidity of pancreatic juice. The reg III gene, whose protein product is pancreatitis associated protein, is induced during pancreatic inflammation. Serum levels of reg III protein are a sensitive marker of severity of pancreatitis. It is an endogenous pancreatic factor that prevents the bacteria infection and scavenges oxygen-derived free radicals. Reg mRNA has been detected in non-pancreatic tissue such as the enterochromaffin-like cells of the stomach, neoplastic tissues of the colon, the small intestine, nervous system, liver tumors, and pituitary. Reg proteins are mitogens to intestinal epithelial cells, pancreatic ductal, beta cells, and Schwann cells, and are likely important to the overall integrity of the pancreas and gastrointestinal tract.

Background

A new family of genes, collectively called `pancreatic reg', has been identified in the gastrointestinal tract. Their name is derived from the isolation of the first gene in the family, now known as reg Iα, from regenerating pancreatic islets. Exciting evidence has been generated implicating reg proteins in normal pancreatic function as well as the pathophysiology of diabetes mellitus, pancreatitis, gastrointestinal neoplasia, and gastric ulceration. In this report, we will review the history of the reg gene family, the many names which each gene's protein product has been called prior to `reg', evidence of reg's role in different pathophysiologic states, and its potential clinical use.

Reg I

The reg proteins were independantly discovered by multiple laboratories over a 13 year period, and finally grouped as a family in 1992 (Table 1). In 1979, De Caro et al of France described that pancreatic stones formed in patients with chronic calcific pancreatitis were dominated by a protein named “pancreatic stone protein” (PSP) (De Caro, et al, 1979, Adrich, et al, 1989). The investigators postulated that abnormal concentrations of it were responsible for protein precipitation and calculus formation within the pancreatic duct. PSP was shown to be a potent inhibitor of calcium carbonate precipitation in pancreatic juice (Multigner, et al, 1983). In 1990, the name PSP was changed to “pancreatic lithostathine” (which means “stone inhibitory” )(Sarles H, et al, 1990). A heavily glycosylated protein, PSP is found in multiple forms in pancreatic juice - dependant on its level of glycosylation.

Table 1.

Discovery of reg Genes and Proteins: A Timeline

1979 human pancreatic stone protein(PSP) De Caro, et al, 1979
1984 rat pancreatitis associated protein(PAP) Keim et al, 1984
1985 human pancreatic thread protein(PTP) Gross, et al, 1985a
1985 bovine PTP Gross, et al, 1985b
1986 rat peptide 23 Yokoya and Friesen, 1986
1988 rat reg gene cloned Terazono, et al, 1988
1989 rat PSP Adrich, et al, 1989
1990 PSP renamed lithostathine Sarles, et al, 1990
1992 rat Reg-2 cloned Kamimura, et al, 1992
1992 human PAP(PAP-H) cloned Orelle, et al, 1992
1992 HIP identified and cloned Lasserre et al, 1992
1993 rat lithostathine gene cloned Dusetti, et al, 1993
1993 rat PAP I and PAP II genes cloned Frigerio, et al, 1993a
1993 human and mouse PAP cDNA cloned Itoch, et al, 1993
1993 mouse reg I and reg II genes isolated Unno, et al, 1993
1993 rat PAP III cloned Frigerio, et al, 1993b
1994 human reg Iα and reg Iβ genes identified Moriizumi, et al, 1994
1994 HIP/PAP genes Lassere, et al, 1994
1994 rat reg as renamed reg I and rat reg III gene isolated Suzuki, et al, 1994
1997 mouse reg III α, reg IIIβ and reglllγ Narushima, et al, 1997
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In 1985, Gross et al characterized a protein in acid extracts of human pancreatic tissue and pancreatic secretions, which spontaneously polymerized into high molecular weight fibrils. Based on this capacity to undergo globule-fibril transformation between pH 5.4 and 9.2, they called it “pancreatic thread protein” (PTP) (Gross, et al, 1985a,b). The amino acid sequence of PTP proteins were eventually found to be closely related to PSP.

At about the same time in Japan, a team directed by Dr. Hiroshi Okamoto was studying the model of islet regeneration induced by 90% pancreatectomy followed by nicotinamide administration (Yonemura, et al, 1984). Using subtraction RNA screening of the regenerating islets, they identified induction of a novel gene encoding a 165-amino acid protein, and named it “pancreatic reg”. Okamoto's group showed that this gene was exclusively expressed in regenerating islets but not in normal pancreatic islets (Terazono, et al, 1988). It was constituitively expressed in pancreatic acinar cells.

In humans, all the above proteins- reg, PSP and PTP, were found to be one in the same (Watanabe, 1990, Gharib 1993), and classified as reg I. Reg I is also found in lower concentrations in the gallbladder mucosa, kidney and stomach (Moriizumi, 1994, Unno, 1993).

New members of the reg I gene family have also been described, and are delineated reg Iα, regIβ, and reg Iγ( (Moriizumi, 1994). Today, human PSP, PTP and reg are delineated reg Iα (Table 2).

Table 2.

Classification of Reg Proteins by Reg Gene Families

Type I mouse reg I
Rat reg I
Human reg Iα, Iβ, Iγ
PSP(lithostathine)
Human PTP
Type II mouse reg II
Type III mouse regIIIα, IIIβ IIIγ
Rat PAP(I)/peptide 23, PAP II and PAP III
Human HIP/PAP
Mouse PAP
Bovine PTP
Rat reg-2
Rat lithostathine
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Adapted from Unno et al (1992)

PAP= pancreatitis associated protein

PTP= pancreatic thread protein

HIP= hepatoma, intestinal and pituitary protein.

Other members of the reg family- reg II and reg III- were subsequently identified (below) (Unno, 1993).

Reg II

In 1993, Unno et al isolated a gene with 76% sequence identity to reg I, and named it reg II. As for reg I, reg II mRNAs were detected in the normal pancreas and regenerating islets, but not in the normal islets (Unno, 1993, Moriizumi, 1994). Rat reg II was isolated by Kamimura (Kimimura et al, 1992) and Suzuki, et al (Suzuki, et al, 1994), respectively.

Reg III

Another gene related to reg I was subsequently isolated which differed from reg II (Suzuki, 1994, Narushima 1997). In contrast to reg I, reg III is expressed weakly in normal acinar pancreas, and induced markedly after inflammation (Narushima 1997). It is also found in the pituitary, small intestine, and hepatomas.

The protein product of reg III had been named and characterized previously. In 1984, Keim et al reported the appearance of a new 16-17KD protein in rat pancreatic juice- not present in healthy rats- after induction of pancreatitis, and named it “pancreatitis-associated protein” (PAP) (Keim et al, 1984). Human PAP was subsequently identified and isolated from the pancreatic juice of patients after pancreatic transplants (Keim V, et al, 1992). In 1992, Orelle et al identified the human gene (Orelle, 1992), and in 1993, human and mouse PAP cDNA were isolated (Itoh, et al, 1993)- all are identical to reg III.

In 1992, Lasserre et al identified a gene which was elevated in 25% of human primary liver cancers. It was named HIP, since its expression is markedly increased in human primary hepatocelluar cancer while it is normally found in the intestine and pancreas (Lasserre et al, 1992). Since HIP and PAP are identical, they are sometimes referred to as HIP/PAP(Lasserre, et al, 1994). They are all identical to the reg III gene.

In 1986, Yokoya and Friesen reported a novel protein from cultured rat pituitary cells whose secretion was increased by growth homone-releasing hormone (GHRH) and decreased by somatostatin (Yokoya S and Friesen HG, 1986). This protein, named peptide 23 is identical to PAP, and, therefore, the protein product of the reg III gene (Tachibana et al, 1988, Katsumata et al, 1995).

New members of the reg III gene family have been described, reg IIIα, reg IIIβ and reg IIIγ( (Narushima 1997), and these correspond to the PAP I, III and III genes isolated by Frigerio (Frigerio 1993). HIP and peptide 23 proteins are now considered the product of the reg IIIα gene.

Human reg IIIα mRNA is expressed very low in healthy pancreas, but at high levels was found in normal small intestine (Itoch, et al, 1993). While reg IIIα is constitutively expressed in the intestinal tract, reg IIIβ mRNA is not (Frigerio, et al , 1993a). The reg IIIγ gene is constitutively expressed in the small intestine and in the pancreas during acute pancreatitis, but not in the healthy pancreas (Frigerio, 1993b). The physiologic significance of these differences is unknown.

The structure of reg genes and proteins

RegIα

Comparison of reg I,II and III genes in the mouse, human and rat has shown that while the sizes of exons and introns vary among the different genes and species, exons 4 and 5 are conserved (Table 3). This region encodes an amino acid sequence motif common to members of calcium dependant (C-type) lectins (Drickamer, 1988), and is the reason behind the theory of reg proteins being lectins.

Table 3.

Comparison of human reg Iα and reg Iβ

Exons/introns reg Iα reg Iβ homology (between reg Iα and reg Iβ) encoding
exon 1 28bp 35bp 58% 5'-UTR
exon 2 110bp 110bp 89% remainder of 5'-UTR and signal sequence
exon 3 119bp 119bp 92% exon3-6 encode the majority of reg protein
exon 4 138bp 138bp 95%
exon 5 112bp 112bp 89%
exon 6 261bp 253bp 79% 3'-UTR
intron 1 301bp 300bp 69%
intron 2 635bp 618bp 71%
intron 3 307bp 307bp 84%
intron 4 715bp 763bp 63%
intron 5 195bp 208bp 69%
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UTR= untranslated region

Table 4 shows the amino acid sequence similarities between some well characterized reg proteins.

Table 4.

Amino Acid Sequence Identity of Characterized Reg Proteins*

Human reg Iα Rat reg Iα Rat reg IIIα Bovine reg III Hamster reg III
Human reg Iα X
Rat reg Iα 68% X
Rat reg IIIα 43 44% X
Bovine reg III 48 47 65% X
Hamster reg III 41 44 61 55% X
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*

Estimated by the Expasy sequence alignment tool.(www.expasy.ch/tools/sim-prot.html)

Figure 1 depicts the general structure of human reg Iα protein. Reg Iα protein is 166 amino acids in length, and contains a hydrophobic signal peptide of 22 amino acids similar to that of other secretory proteins (Gharib, et al, 1993, Giorgi, et al, 1989, Terazono, et al, 1988, Moriizumi, et al, 1994, Padgett, et al, 1986). It has 7 cystine residues, whose position is highly conserved between all homologues and all species. After secretion, the N-terminal undecapeptide is cleaved at an arginine-isoleucine site by trypsin.

Figure 1.

Figure 1

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Schematic of human reg Iα (PSP/lithostatine/PSP), with delineation of common motifs with other reg proteins across species. There is a 25 amino acid signal peptide which is cleaved prior to secretion of the protein. An 11 amino acid undecapeptide is cleaved intra-luminally by trypsin yielding a 133 amino acid protein. In human and rat reg I the undecapeptide confers inhibition of calcium carbonate precipitation. The 133 amino acid protein forms high molecular weight thread-like structures in vitro. The portion which is thought to confer the mitogenic acitivity to β- and epithelial cells is underlined. The 6 cystines, conserved in all reg molecules, are also underlined. In reg III proteins, a five amino acid insert is found as noted.

The N-terminal undecapeptide released from the secreted reg Iα protein after cleavage by trypsin after has been identified as the protein fragment which prevents calcium carbonate precipitation (Multigner et al 1893, Adric et al 1991, Bernard et al 1992). The C-terminal cleaved large fragment of reg Iα polymerizes at neutral pH into a high molecular weight threadlike structure. It is also the fragment which confers mitogenic activity on epithelial cells.

Also depicted in Figure 1 is a feature which distinguishes reg I from III proteins- the latter contains a 5 amino acid insert at about position 107-112.

Genomic mapping has shown that in humans, the reg I, II and III families are tandemly ordered in 95kb DNA region of chromosone 2p12 (Miyashita, et al, 1995). In mouse, reg I, reg II and reg III are located on mouse chromosome 12, 3 and 6C respectively (Table 4) (Unno, et al, 1993; Narushima, et al, 1997).

Reg II

Rat reg II mRNA are transcribed into a protein of to 177 amino acids. Analysis of the amino acid sequence reveals a 60% identity to rat reg Iα, and 61% identity to human regIα. These similarities include conservation of all seven cystine residue positions, and the N-terminal undecapeptide cleavage sequence (Kamimura, et al, 1992, Unno, 1993).

Reg III

Rat reg IIIα cDNA encodes a 174 amino acid protein with a 25 amino acid signal peptide. The deduced sequence has only 42.2% identity with rat reg Iα. Human reg IIIα protein has only 69% sequence identity with rat reg IIIα(Itoh and Teraoka, 1993). The reg III family has the unique 5-aa insertion in C-terminal region (amino acid residues 110-114) (Susuki, et al, 1994) .

The Pancreatic Thread Protein (PTP) issue

Human and bovine PTP proteins were isolated by similar methodology by the same group (Gross et al, 1985a, b; de la Monte et al 1990). But, while bovine PTP protein is a member of the reg III family, amino acid sequence has shown that human PTP is actually identical human PSP, or reg Iα (Watanabe, et al, 1990).

Structural analysis of bovine PTP protein has shown that it contains two polypeptides linked by two disulfide bridges. The A chain consists of 101 amino acid residues with a molecular weight of 11,073 and a B chain of 35 residues with a molecular weight of 3970 (Cai, et al, 1990). Whether this configuration is found in other reg proteins has yet to be determined.

The Structure of Reg Proteins

Itoh et al studied recombinant reg Iα protein, and mapped the secondary structure of α-helix and β-sheet contents, as well as intramolecular cysteine bridges (Itoch, et al, 1990, Renugopalakrishnan, et al, 1999) (Figure 2). Analysis of a computer model based on other calcium dependant lectins has concluded that the three dimentional characteristics of the protein really do not support sugar- or calcium-binding properties (Patard, et al, 1996). We actually confirmed this in vitro- reg I protein does not bind galactose or mannose (Zenilman et al, 1998b).

Figure 2.

Figure 2

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Model of human reg Iα protein based on high resolution NMR spectroscopy. It is composed of two α-helices(H1 and H2), five extended strands (S1-S5) and six non-conserved loops of undefined structures (L1-6) (reprinted with permission from Patard et al)

The Function of Reg Proteins

Reg Iα and the β-cell

Although constituitively expressed by the pancreatic acinar cell reg Iα gene expression is linked to that of the β-cell. It is induced in regenerating islets after pancreatectomy, in hypertrophic islets, and in islets recovering from diabetes (Ishii, 1993). In the regenerating β-cell, reg Iα protein co-localizes with the insulin secreting granules (Terazono, et al, 1990).

During pancreatic embryogenesis, reg Iα gene expression is also linked with development of the islet. In humans Mally et al observed very low expression of reg Iα mRNA between the 13th and 16th weeks of gestation, an early stage in islet differentiation. Similarly, they noted a marked upregulation of the gene between 16 and 24 weeks; this coincides with cellular expansion of β-cell mass (Mally, et al, 1994). Furthermore, Moriscot et al observed a significant correlation between the expression of reg Iα and insulin genes in embrogenesis at 17 to 29 weeks, but no relation with other pancreatic genes (such as trypsinogen, chymotrypsinogen, lipase, glucagon or somatostatin) (Moriscot, et al, 1996).

Others have shown significant relation between reg Iα and the β-cell function. Miyaura showed that during hyperinsulinemia ofter subcutaneous implantation of insulinoma, there is reduced β-cell mass, and reduced reg Iα expression. Subsequent removal of the insulinoma induced β-cell proliferation, which was preceded by reg Iα gene induction (Miyaura, et al, 1991). In vitro studies have shown that exposure of cultured rat islets to growth factors induced reg Iα gene expression (Francis, et al, 1992).

Our laboratory observed that in the aging mouse, the normal decline of insulin mRNA levels seen with age is closely paralleled by decreased reg gene expression. Therefore, the islet dysfunction of aging is linked to depressed expression of the exocrine product reg (Perfetti, et al, 1994). This is potentially important since the acinar cells normally atrophy with age, and a link has been established between physiologic acinar atrophy and progressive islet dysfunction (unpublished observations).

Decreased levels of pancreatic reg Iα mRNA have been associated with islet failure and diabetes. In the non-obese diabetic (NOD) mouse, there is a correlation between low reg gene expression in the pancreas and the likelihood of subsequently developing diabetes (Baeza, et al, 1996).

The expression of reg Iα has been studied in other models of islet proliferation. Non-occlusive wrapping of the pancreas is a potent stimulus that leads to the induction of duct epithelial cell proliferation followed by endocrine cell differentiation and new islet formation. In hamster and rat models, reg Iα gene expression increases within 1 to 2 days after wrapping and then decreases, returning to basal between 4 and 6 days after wrapping (Rafaeloff, et al, 1995, Zenilman 1996a). At this time, expansion of the ductular cell population is noted, these ducts differentiate into islets. These data suggest that reg may be a paracrine effector of duct cell proliferation, the initial step of pancreatic regeneration and islet neogenesis.

Although reg Iα protein is normally an exocrine-cell derived product (Sarles 1990, Zenilman 1996a), we have shown that even in the adult, its expression is not related to exocrine gene expression (Zenilman, 1997a, 2000). Further experiments have shown that its expression is linked to the endocrine pancreas (Perfetti, et al, 1994). This supports the hypothesis that reg Iα is an exocrine product that is involved in β-cell function.

We have recently observed that reg Iα protein is a mitogen to both pancreatic ductal and β-cells. This is true on both transformed cells and primary ductal cells in culture (Figure 3) (Zenilman, 1996b, 1998a). Others have confirmed this (Otokoski 1994, Watanabe 1994). Recent data from our lab and others suggests that reg activates mitogen-activated kinases with in both ductal and intestinal target cells (unpublished observations).

Figure 3.

Figure 3

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Reg proteins (Iα and IIIα) have been shown to be mitogenic to gastrointestinal epithelial cells (pancreatic ductal, gastric mucosal, intestinal mucosal), pancreatic beta-cells, and schwann cells. This figure depicts the mitogenic activity of rat reg Iα on the rat pancreatic ductal cell ARIP and primary cultures of rat pancreatic ducts, after 72 hour incubation. ARIP cells were assayed by thymidine incorporation, ductal cells by incorporation of bromodeoxyuridine (adapted from Zenilman et al 1998).

The value of reg Iα protein as a therapeutic tool in diabetes has recently been explored. Watanabe et al treated pancreatectomied rats with recombinant reg protein (1 mg/kg per day, intraperitoneal) for 2 months and successfully reversed diabetes (Watanabe, et al, 1994). In a model of spontaneous diabetes in the NOD mouse, the administration of recombinant reg Iα protein with linomide (quinoline-3-carboxamide) also ameliorated diabetes (Gross, et al, 1998). We have also observed improved glucose tolerance in animals with chronic pancreatitis after administration of human reg Iα protein (unpublished observations).

However, the role of reg Iα in β-cell growth and pancreatic regeneration has been challenged, using two well-defined models of pancreatic β-cell growth in mice - 90% pancreatectomy and chronic glucose infusion. In the former model, investigators noted a rapid induction of reg in the remnant pancreas of operated and sham-operated controls. It seems that the stress of sham-operation alone can induce the gene. In the chronic glucose-infused rat, islet hyperplasia was observed, but without an increase in reg gene expression. These data suggest that reg Iα is not critical for all models of islet hyperplasia (Smith, 1994, Christofilis, et al, 1997).

Reg Iα and Pancreatic Differentiation

Reg Iα gene expression has been implicated, but not proven to be, involved in pancreatic differentiation. Since it is found in regenerating acinar tissue after pancreatitis, Rouquier et al proposed that reg Iα mRNA is expressed within pancreatic acinar cells during the de-differentiated state (Rouquier, et al, 1991). Our group used in vitro methods to show that expression of reg mRNA does indeed inversely correlate with the level of pancreatic acinar cell differentiation (Zenilman, et al, 1997a).

Unfortunately, exogenous administration of reg Iα protein has had no effect on the ability of the β-cell or ductal cell to differentiate. Specifically, after incubation of rat β- and ductal cells with reg Iα protein we observed no change in with insulin gene expression or insulin secretion (Figure 3) (Zenilman 1996d).

Thus, induction of the reg Iα gene in the acinar cell may be related to the that cells' differentiated state, and secretion of the protein may result in proliferation of surrounding ductal and β-cells. Induction of reg Iα within the β-cell is likely only associated with a stimulus for that cell to proliferate (Otonkoshi,et al, 1994).

Reg I and Pancreatic Tumors

Immunohistochemistry of pancreatic tumors has confirmed the presence of reg Iα protein was observed in acinar cell carcinomas, pancreatoblastomas, cystic tumors, but not in endocrine tumors. It was also found in 25% of duct cell adenocarcinomas, but this imunoreactivity may simply be phenotypic heterogeneity and not clinically important(Kimura, et al, 1992).

Reg III and Pancreatitis

Reg IIIα mRNA and protein are not typically found in normal pancreas, but increases markedly during inflammation (Orelle, et al, 1992, Iovanna 1991). Reg IIIα mRNA is rapidly induced by other stresses, such as hypoxia and alcohol (Mckie, et al, 1996). Serum levels of the protein have been shown to be a useful marker for acute pancreatitis (Keim, et al, 1992, Iovanna 1994, Zenilman, 1999).

Studies have shown that reg IIIα protein is able to aggregate bacteria in vitro and prevent their proliferation (Iovanna et al, 1991). A possible role for the protein would therefore be to protect the tissue against bacterial infection during the period in which inflammation and necrosis increase the risk of bacterial contamination (Keim, et al, 1994).

Alternatively, Ortiz et al noted that reg IIIα protein can protect cell damage induced by oxygen-derived free radicals. They noted transfection of AR4-2J acinar cells with reg IIIα gene conferred significant resistance to apoptosis induced by low doses of hydrogen peroxide. This suggests that during oxidative stress, reg IIIα is part of a mechanism of pancreatic cell protection against apoptosis.

We found that bovine PTP protein, which is reg III, is also a mitogen to pancreatic derived cells (Zenilman 1996b), implicating it in the proliferative response of ducts to pancreatic injury.

Ectopic expression of reg

Reg and the Nervous System

Reg Iα protein is present in the central nervous system of normal individuals at low levels, and is higher in fetal and infant tissue. In patients suffering from Alzheimer disease and Down's Syndrome, local reg Iα levels is increased (Ozturk, 1989). It is believed that reg Iα expression might be related to neuronal sprouting and regeneration (de la Monte, 1990).

Livesey et al found that Reg-2 (reg IIIα) protein is a potent Schwann cell mitogen. Since Schwann cell proliferation is essential for neural regeneration, reg potentially is an important participant as well. In vivo, reg IIIα protein was found to be transported along regenerating axons, and inhibition of its genetic signalling significantly retarded the regenerating capacity of axons.

Reg and the Stomach

Reg Iα mRNA is induced in the gastric mucosa of rats after the stress of cold water immersion, and has been localized to the cells of healing gastric ulcers (Asahara, et al, 1996). Reg Iα has also been localized to gastric enterochromaffin-like (ECL) cells, which secrete gastrin. In situations of chronic hypergastrinemia reg Iα gene expression increases. Gastrin itself is a potent mucosal mitogen, opening up the possibility that reg Iα may modulate gastrin-induced mucosal cell growth (Fukui, et al, 1998)

Reg and the Eye

Fredj-Reygrobellet et al postulated that reg Iα protein would localize to structures which undergo continuous and rapid renewal. They investigated the presence of reg Iα protein in eyes and extrocular structures of rabbits, monkeys and man. While not found in eyes from aged donors, it was strongly expressed in young donor eyes and in regenerating corneal epithelium. These findings enforce the hypothesis about the involvement of reg Iα protein in cell proliferation (Fredj-Reygrobellet et al, 1996).

Reg and Colonic Mucosa/Neoplasia

While not normally found in colonic tissue, human reg Iα has been found in tumoral tissues of the colon and rectum. The ectopic expression of human reg in certain types of tumors suggests the human reg protein may be related to tumorigenesis (Watanabe, et al, 1990). Using immunohistochemical technique we localized reg Iα expression to 53% of colonic tumors, but 100% of the normal-appearing mucosa adjacent to the cancer, called the transition zone (Zenilman, et al, 1997b). We have also observed its ectopic expression in colonic tissue at risk for neoplasia, specificially familial adenomatous polyposis and chronic ulcerative colitis (Levine 1999). Enhanced reg protein expression maybe related to the proliferate state of tumor cells or cells at risk for becoming tumorous, and it may even be a mitogen to the neoplastic mucosa. We have been able to assay reg protein levels in the colonic effluent taken during colonoscopy (Tobi, et al, 1997), but found that it will be unlikely that such an assay will be useful as a marker of colorectal neoplasia.

Reg the Pituitary

Peptide 23 (reg IIIα) protein is secreted by rat anterior pituitary cells in primary culture, and may therefore have some role in pituitary cell proliferation (Katsumata, et al, 1995).

Reg and the Liver

HIP/PAP (reg IIIα) mRNA is expressed at a high level in the tumors 25% of human hepatocellular carcinomas, but is not detected in normal fetal or adult liver, or in regenerating rat liver (Lasserre, et al, 1992). After secretion, it interacts with rat hepatocytes in the extracellular matrix. This suggests that reg IIIα protein may be of potential importance to liver cell differentiation or more likely proliferation (Christa, et al, 1996).

Summary and Future Projects

We have shown that the reg family is comprised of a number of genes and protein products which have been identified as a number of other names over the last 15 years (Table 2). The reg protein amino acid sequence resembles calcium dependent lectins. They are differentially expressed in cells of the gastrointestinal tract. In the pancreas, reg may be a dual purpose protein: an inhibitor of stone formation and mitogen to epithelial cells. Expression studies suggest reg protein to be a marker of stress and regeneration. Reg Iα and II are expressed in reponse to β-cell inflammation. Reg IIIα is induced after pancreatic inflammation, and is a useful marker for severity of pancreatitis.

Future studies on the role of reg Iα include elucidation of its mechanism of action in islet ontogeny and use as a therapeutic agent for islet failure. Future studies on reg IIIα will focus on its use as a marker of pancreatic inflammation, and the mechanism of its protective effect on the pancreas during pancreatitis. Finally, identification of the reg receptor(s) will elucidate information about the role of the reg family in maintaining gastrointestinal and endocrine integrity.

Figure 4.

Figure 4

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Although the reg Iα gene is induced during islet neogenesis and its protein is mitogenic to pancreatic ductal and beta cells, it does not affect insulin gene expression or secretion. This figure depicts the effect of reg Iα on rat pancreatic islet insulin secretion. Islets (40/well) were cultured in the presence of 10-8 M reg Iα (hPTP) or reg IIIα (bPTP) or prolactin (1 ug/ml, an insulin secretagogue obtained as a gift of the National Hormone Project) for 5 days. Media was changed daily and then assayed for insulin by ELISA. Cumulative insulin secretion was increased by Prolactin, but not by reg proteins. Reg proteins have no effect on the ability of β-cells to secrete insulin.

Acknowledgments

This work is supported by NIH grant(RO1-DK54511-01 ).

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