regenerating genes and their possible roles in functions - wjpps

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Wang et al.

World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 5.210

Volume 5, Issue 01, 207-224

Research Article

ISSN 2278 – 4357

REGENERATING GENES AND THEIR POSSIBLE ROLES IN FUNCTIONS Martin Omondi Alfred1 and Min Wang1,2,* 1 2

School of Life Sciences and Technology, China Pharmaceutical University, Nanjing,

State Key Laboratory of Nature Medicines China Pharmaceutical University, Nanjing, China.

Article Received on 16 Nov 2015, Revised on 06 Dec 2015, Accepted on 28 Dec 2015

ABSTRACT Reg family proteins were discovered in the search for factors involved in pancreatic islet cell regeneration. They constitute a family belonging to calcium dependent lectin (C-type lectin) gene super family. They represent a group of small secretory proteins, which can function as

*Correspondence for

lectins, acute phase reactants, growth factors or anti-apoptotic factors

Author

for pancreatic β-cells, neural cells and epithelial cells in digestive

Min Wang School of Life Sciences

system. They play a wide range of roles in human physiology and

and Technology, China

diseases as well as in other mammals. Special attentions have been

Pharmaceutical

paid to the regeneration of pancreatic β-cells and administration of Reg

University, Nanjing,

proteins and/or activation of the Reg ever since Regs were discovered

genes to be used as potential therapeutic approaches for diabetes. Successively, the potential role of Reg family in tumors especially in digestive tract has drawn more attention. This review article therefore focuses on the members of Reg family, their role in diabetes, cancer, signaling and their possible functions and mechanisms. KEYWORD: They constitute a family belonging to calcium dependent lectin (C-type lectin) gene super family. INTRODUCTION Over the past three decades, considerable attention has focused on the Reg (regenerating) gene family, which belongs to the calcium-dependent lectin superfamily, encoding a group of small multifunctional secretory proteins. [1] Reg family proteins are primarily involved in cell proliferation and differentiation, inflammation, diabetes, and carcinogenesis. [2] Identified members of the Reg multi gene family in human include Reg1α, Reg1β, Reg3α, Reg3β and www.wjpps.com

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Reg4. Three of the four genes except Reg4 are organized in six exons with similarities observed in their coding sequences extend to their promoter regions, suggesting possible common mechanisms of activation. In addition, these three genes are located at the same position on chromosome 4q33–34 with Reg4 located on chromosome 1p13.1-p12, suggesting that they are derived from the same ancestral gene by gene duplication. [3] Pancreatic stone protein/reg2 and its related homolog pancreatitis associated protein/Reg3 share highly conserved amino acid sequences. This has mainly been studied in the pancreas and is prominently upregulated in acute or chronic pancreatitis. [4] Reg gene is also involved in differentiation and proliferation of the hepatic[5], pancreatic[6], gastric cancer[7] and intestinal cancer cells.[8] Initially, PSP/Reg2 was suggested as a sensitive marker of pancreatic injuries, however, other conditions such as acute stress might activate the secretion of PSP/Reg. [4] Recent data revealed that Reg could discriminate patients with infection, infection with sepsis and no infection, which might be a superior marker for posttraumatic complications. [9] These studies have also reported significantly elevated PSP/reg2 levels in blood of patients with sepsis, VAP, COPD exacerbation and peritonitis.[10] Reg and PARP In rats, administration of poly (ADP-ribose) synthetase /polymerase (PARP) inhibitors such as nicotinamide after a 90% pancreatectomy caused a drastic increase in islet regeneration or expansion and this was thought to be driven by novel growth factors. (PARP is a chromatinbound DNA repair enzyme). As it was initially discovered, PARP inhibitors (i.e. nicotinamide, which promotes islet cell growth) activate Reg1 gene transcription. [11] PARP is an important enzyme involved in DNA repair; bound to the DNA cis-elements, it also affects the transcriptional DNA/protein complexes. The autopoly (ADP-ribosyl) action of PARP in the complex inhibits the DNA/protein complex formation, thus PARP inhibitors enhance the DNA/protein complex formation and Reg gene transcription. Interestingly, PARP activation leads to β-cell death. (PARP is also a substrate of pro-apoptotic caspase-3 which causes PARP cleavage from 116 to 89 kDa). Autoimmune and streptozotocin-induced attacks on pancreatic islet cells lead to elevated production of nitric oxide (NO) and reactive oxygen intermediates (ROI), which induce widespread DNA strand breaks and PARP activation and further interact with Reg genes transcription (fig. 1). [12]

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Figure 1: Representation of the unified role of PARP in the Reg gene transcription and DNA repair (adapted from[11,12]).β-cells are affected by many factors, such as immunological abnormalities, viruses, irradiation, and chemical substances leading to local inflammation in and/or around pancreatic islets. [11] (1): Inflammatory mediators such as IL-6 and glucocorticoids are produced in the inflammation process. IL6/glucocorticoid stimulation induces the formation of an active transcriptional complex for Reg, in which PARP is involved, and when the PARP is not poly (ADP-ribosyl) ated in the presence of PARP inhibitors, the transcriptional complex is stabilized and the Reg gene transcription is maintained. (2): DNA-damaging substances such as superoxide (O2.) and nitric oxide (NO.) are frequently produced in inflammatory processes. When the DNA is damaged, PARP senses DNA nicks and autopoly (ADPribosyl) ates itself for the DNA repair. Once PARP is auto-poly (ADP-ribosyl) ated, the formation of the Reg gene transcriptional complex is inhibited, interfering with the interaction between PARP and other nuclear proteins necessary for the active complex, and therefore the transcription of Reg gene stops. (3): When DNA is massively damaged, PARP is rapidly activated to repair the DNA, and the complex for Reg gene transcription is not formed at all.[12,13] According to the Okamoto model, the resulting activation of PARP depletes intracellular NAD+ and energy in repairing the DNA strands, leading to cell death by necrosis. Indeed, streptozotocin-induced NAD+ depletion and cell death are dependent on increased PARP activity (fig. 2).[12] Conversely, PARP gene deletion enabled mice resistant to streptozotocininduced cell death and diabetes; and inhibitors of PARP (such as 3-amino benzamide or nicotinamide) have long been known to protect islet cells. [14] The relationship becomes more

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complicated as streptozotocin-induced diabetes (with activated PARP) also induces Reg gene expression significantly further suggesting involvement of the Reg family proteins either in islet cell death or protection[12,14]

Figure 2: Roles of PARP and its inhibitors for cell death, regeneration, and functioning (adapted from[14]). PARP activation causes NAD depletion to form poly (ADPR), resulting in necrotic cell death. However PARP inhibitors induces three important events in cells: PARP inhibitors prevent the necrotic cell death, keeps PARP functional as a transcription factor for cell regeneration, and maintain the formation of a second messenger, cADPR, to achieve the cell functions. Reg genes and pancreatitis A rapid and massive rearrangement of the pattern of pancreatic gene expression has been observed during the acute phase of pancreatitis. [15] A moderate increase has also been observed for Reg 2 (lithostathine), the only described pancreatic protein with significant structural similarity to the Reg1. [4,16] In addition, Reg1 and Reg2 has displayed marked homology with the carboxy-terminal region of C-type animal lectins, which probably explains their capacity for aggregating bacteria. The spectacular upregulation of Reg1 and Reg2 during pancreatitis and their properties of defending bacterial proliferation suggest that these proteins are important components of the mechanism of defense against pancreatic aggression.[10] Previous studies, have demonstrated the presence of a factor such as stress in serum from rats with acute pancreatitis, but not from healthy rats, capable of inducing Reg gene expression in the pancreatic acinar cell line AR-42J.[17] Thus, during acute pancreatitis there is a decrease of pancreatic function, but a well-defined response of the gland characterized by specific alterations of protein synthesis that are regulated at transcriptional

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as well as post-transcriptional levels, involving Reg genes.[16] This suggests that in pancreas, Reg gene could mediate a stringent emergency program that enables the survival of the gland or the organism under the situation of acute stress. [18] Roles of Reg genes in diabetes Under abnormal conditions, impaired islet function ultimately leads to diabetes mellitus; as an insufficient islet β-cell mass is the main contributing factor of autoimmunity-induced type 1 (T1DM) and a key element in type 2 diabetes (T2DM) associated with insulin resistance.[19,20] In the last decade or two, various growth factors have been shown to stimulate islet cell growth and their effectiveness has been published in several articles. [21-23] For a therapeutic purposes, β-cell mass can also be supplemented by islet transplantation where growth factors have been found to promote the survival and/or expansion of transplanted cells in rodents.[24] Frequently, T2DM is only diagnosed when complications occur. The increasing prevalence, serious complications, and high-undiagnosed rate make T2DM an important field of research. Two major defects play a crucial role in disease progression of T2DM: insulin resistance (IR) and β-cell failure or eventual loss of β-cell mass. Approximately, 80 % of the IR patients are able to compensate, at least for a period of time, due to the β-cell capability of compensating with hyper insulinemia to overcome IR, probably associated with Reg genes expression.[25] Studies have also shown that circulating Reg values correlate with diabetes duration which implies that there is a positive correlation between Reg levels and the course of diabetes. Under normal situations, the most predominant origin of Reg is pancreatic acinar cells, while other tissues, intestines and islets for instance, and appear to produce Reg predominantly under pathological conditions. It is reported that Reg proteins are associated with islet regeneration. Reg appeared to boost β-cell growth and regeneration by induction of cellular proliferation. Reg2 has also been found to be altered in the condition of sepsis[9,26], chronic obstructive pulmonary disease (COPD) exacerbation[9], and posttraumatic complications[27], which indicated that Reg might serve as a reflection of infectious conditions and organ failure Moreover, elevated Reg level has been observed in both of the disease progression state of hepatocyte nuclear factor 1 alpha (HNF1A)–maturity onset diabetes of the young (HNF1AMODY) and the type 1 diabetes mellitus (T1DM) human subjects. [28] Patients with diabetes have significantly elevated Reg levels, and it is worth noting that this trend has been observed in the high-risk groups.[29]

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In diabetes, islets are infiltrated by inflammatory cells. To counteract such attacks, high levels of Reg are secreted to boost islet cell proliferation, as strong Reg immune reactivity in perivascular and peri insular areas have been observed. Recent study in insulinoma cell lines and mouse models provided biological evidence that β-cells undergoing apoptosis induce the Reg expression in surviving neighboring β-cells.[30,31] The role of inflammation in the pathogenesis of T2DM and associated complications has been well established, and Reg protein mainly reflect the progress of inflammation. [28,30] These studies further confirmed that Reg levels show close associations with diabetes and imply that Reg might be a promising sensitive marker or therapeutic agent of diabetes in future. It might indicate that diabetes progression might remain at a stable level during those periods. As a result, this may provide a strategic period to intervene and hence postpone or even prevent the onset of T2DM. Similar studies have also found a correlation between Reg levels and glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (2hPG) which indicated that the elevation of Reg levels might play an important role in the development of abnormal glucose tolerance. [32] This observation is in agreement with recent data indicating that increased extracellular glucose concentrations potentiated Reg gene expression, which may represent an important physiological feedback loop for the regulation of β-cell mass.[33] As Reg genes were identified as being related to glucose homeostasis, the CD38-cADPR signal system for insulin secretion by glucose should be mentioned. In cells, glucose increases the intracellular Ca2+ concentration to cause the secretion of insulin. Ashcroft et al., proposed in 1984 that the increase in Ca2+ is provided extracellularly.[34] This implied that the process of glucose metabolism has a direct relation to the millimolar concentration of the voltage-dependent Ca2+channels.[35] Okamoto model illustrated that the decrease in the NAD level cause decreases in cADPR in cells, which is also associated with Reg proteins and PARP. This was further confirmed by Takasawa et al., in 1993 that insulin secretion by glucose occurs via cADPR-mediated Ca2+ mobilization from an intracellular Ca2+ pool, the endoplasmic reticulum as shown in fig.3 that is, because ATP inhibits the cADPR hydrolase of CD38, there is accumulation of cADPR which acts as a second messenger for Ca 2+ mobilization from the endoplasmic reticulum release. [36] Thus, PSP/reg is significantly upregulated in diabetes, and the PSP/reg level is related to the duration of diabetes. Therefore, PSP/reg might be useful as a predictor or therapeutic agent against diabetes. [28]

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Figure 3. The CD38-cADPR signal system for insulin secretion by glucose stimulation in β-cells (adapted from[12]). In CD38, Glu-226 is essential for ADP-ribosyl cyclase, and Cys-119 and Cys-201 are essential for cADPR hydrolase. Lys-129 is the cADPR binding site and is essential for cADPR hydrolase. ATP competes with cADPR for the binding site (Lys129), inhibiting cADPR hydrolysis, which causes the accumulation of cADPR. cADPR binds to FKBP12.6 to release Ca2+ , dissociating FKBP12.6 from ryanodine receptor (RyR). CaM kinase II phosphorylates RyR to sensitize and activate the Ca 2+ channel. Ca2+, released from intracellular stores and/or supplied from extracellular sources, further activates CaM kinase II and amplifies the process. In this way, Ca 2+ induced Ca2+ release can be explained. Reg in tumor Increasing evidence suggest that Reg genes are important regulators of gastrointestinal (GI) carcinogenesis. Among these human Reg genes, the upregulation of Reg4 expression has frequently been observed in many GI malignancies including gastric [37,38], pancreatic[39] and colorectal cancer (CRC)[8] Previous studies have suggested that Reg4 may take part in early carcinogenesis in certain cancers. Many colorectal cancers develop through the ‘adenoma to carcinoma sequence’ model[40], in which adenomas are recognized as precursor lesions of the vast majority of colorectal cancers. Zhang et al. found that Reg4 was expressed in both colorectal adenoma and adenocarcinoma[41] This result constituted further evidence that overexpression of Reg4 may be an early event in the colorectal adenoma-carcinoma sequence and carcinogenesis, and its detection may be useful in the early diagnosis of colorectal adenoma formation.[42] An increase in Reg4 expression has also been observed in human

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colon cancer cell lines selected for in vitro resistance to the cancer chemotherapeutic agent 5FluoroUracil (5-FC).[43] Reg4 may also protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signaling pathway. [44] Therefore, Reg4 and associated signaling pathways for example Akt signaling pathway could be a potential target for adjunctive treatments of human cancers. [45] Whether Reg4 is associated with tumor clinicopathological features is still not well understood. Violette et al. reported that there was no significant relationship between Reg4 and the TNM state of the tumors or their localization. [46] But Yamagishi et al. suggested that Reg4 staining was observed more frequently in stage III/IV cases than in stage I/II cases, and patients with Reg4 positive gastric cancer tended to show a poor outcome, although not to a statistically significant degree.[47] In contrast to gastric carcinoma, expression of Reg4 by colorectal carcinoma is associated with lymph node metastasis. Numata et al. showed that high expression levels of Reg4 were correlated with well-differentiated histological type, deeper invasion, presence of lymphatic invasion, presence of liver metastasis, and advanced stage (stage IV).[48] Oue et al. reported that Reg IV expression was associated with delayed liver metastasis of colorectal cancer[49], and inhibition of apoptosis by Reg4 may participate in liver metastasis. It has also been reported that Reg IV induces the expression of matrix metalloproteinase-7 (MMP-7)[50], which promotes liver metastases.[51]. Therefore, targeting to Reg protein is a promising adjuvant to current therapies of pancreatic adenocarcinoma, colorectal adenocarcinoma and adenoma and gastric cancer. Reg and apoptosis Many recent studies have suggested that inflammation plays important roles in the development of various cancers. Signal transducer and activator of transcription 3 (STAT3), a major transcription factor for transmitting inflammatory cytokine signals to the nucleus, has been shown to promote cell proliferation and anti-apoptosis.[52] Thus, STAT3 activation is suggested to be involved in carcinogenesis under a background of inflammation. To further support these studies, Judd et al. have reported that STAT3 hyper activation develop gastric tumors in association with chronic gastritis. [53,54] Past studies have also clearly demonstrated that the STAT3/Reg1α pathway has a significant role in anti-apoptosis of gastric cancer cells. These studies showed that Reg1α protein mediates the anti-apoptotic effect of STAT3 signaling via activation of the Akt/Bad/Bcl-xL pathway.[55] However, it has been reported previously that STAT3 activation can directly

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enhance the expression of Bcl family proteins in myeloma, leukemia and intestinal epithelial cells.[56] In addition to Reg1α protein, STAT3 activation appears to enhance other antiapoptotic molecules such as survivin or inhibitor of apoptosis protein-2 (IAP2).[57,58] These findings appear to be reflected in current studies, that have shown that Reg induction is partly but not completely rescued gastric cancer cells from apoptosis by STAT3 inactivation. However, since Reg1α protein induces strong activation of Akt and enhancement of Bcl-xL expression in AGS cells, it is probably that Reg1 protein as downstream molecule of STAT3 signaling, plays an important role in anti-apoptosis of gastric cancer cells.[55] It has also been reported that recombinant Reg4 increases expression of Bcl-2.[50] B-cell lymphoma-2 is an antiapoptotic protein located on mitochondria and is expressed at high levels in some tumor cells and tissues. In the mitochondrial pathway, antiapoptotic Bcl-2 family proteins prevent mitochondrial membrane permeabilization and thereby inhibit changes in the mitochondrial membrane potential and cytochrome C release. Mitani et al. suggested that overexpression of Reg4 may suppress 5-FU-induced apoptosis by inhibiting the mitochondrial apoptotic pathway.[59] It has been reported that AP-1 induces expression of dihydropyrimidine dehydrogenase (DPD) [60], which is an initial and rate-limiting enzyme in 5-FU catabolism, and has significance for the pharmacokinetics and toxicity of 5-FU. Overexpression of DPD in tumor cell lines is associated with resistance to 5-FU.[61] Mitaniet al. confirmed that Reg4 inhibits apoptosis by activating the EGFR/Akt/AP-1/DPD signaling pathway, inhibiting 5-FU Site. This strongly indicated that Reg proteins are associated with drug/radio- resistance in tumor cells. In summary, Reg4 can confer resistance to 5-FU-induced apoptosis in colorectal cancer and gastric cancer. At least two mechanisms are involved in inhibition of apoptosis by Reg4, including Bcl-2 and DPD. Bishnupuri et al. reported that Reg4 is a potent activator of the EGFR/Akt/AP-1 signaling pathway in human colon cancer cell lines. [50] Interestingly, Nanakin et al. found that EGF and TGF-α enhanced Reg4 gene expression by the extracellular signal-regulated kinase (ERK) signaling pathway in the SW403 cells line [62], and high phospho-ERK expression is associated with a lower survival rate of colorectal cancer. [63] These studies suggest that a positive expression feedback loop between EGF and Reg4 exists in the signaling pathways. Thus, disruption of Reg4/EGFR signaling may have utility as a novel therapeutic intervention for human gastrointestinal cancer. www.wjpps.com

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Signaling pathway of Reg GSK-3β, a key enzyme regulating β-Catenin phosphorylation is a known downstream transducer of the PI3K-Akt

signaling pathway.[64,65] GSK-3β

phosphorylation in response to PI3K-Akt signaling.

[66]

is inactivated by

It has previously been reported that

Reg4 mediates induction of epidermal growth factor receptor (EGFR)-Akt-AP-1 signaling in human cancer cells.[50] Another study revealed that Reg4 mediates regulation of GSK-3β and β-Catenin phosphorylation and TCF4 transcriptional activities. [67] This provides a link to the multi protein degradation complex. Furthermore, GSK-3β and β-Catenin are involved in regulation of Cyclin D expression and plays vital role in regulation of cell proliferation of many human tumors.[50,67] Past studies showed that Reg4 mediates increase in expression of cell cycle regulatory genes Cyclin D1 and D3, and associated kinases in human cancer cells.[68] In addition, Cyclin D1 promoter also includes binding sequence for AP-1 transcription factor and Reg4 mediates increase in previously reported AP-1 transcriptional activity might be an important event to regulate Cyclin D1 expression in human CRC cells.[69] These studies confirms Reg4 as potent modulator of Akt-GSK-3β-β-Catenin-TCF4 and EGFR-Akt-AP-1 signaling pathways, which often results in altered expression of genes associated with human tumors cell proliferation and apoptosis. When pancreatic ductal and β-cells are exposed to exogenous Reg1 protein, proliferation occurs, in conjunction with induction of genes involved in the cell cycle.[70] Previous data indicated that, in pancreatic ductal cells exposed to Reg1 protein, signal transduction pathways involving the MKPs and cyclins are induced. [71] Studies have in the past confirmed that MKP-1 gene expression and cyclin D1 are induced by Reg1 (fig. 4). Takasawa et al., showed that cyclin D1 is activated within 60 min of exposure to Reg1 by phosphorylation of ATF-2 by a phosphoinositide-3-kinase (PI(3)K)-dependent pathway.[68] Also, Kadowaki et al., showed that Reg1 is mitogenic via the classical MAPKERK1/2 pathway. [72] Thus, proliferation stimulated by Reg proteins could be initiated via multiple signaling pathways

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Figure 4. Proposed mechanism of action of pancreatic. Reg1 on duct cells (Adapted from[71]). Exogenous Reg1 binds the exostosin-like glycosyltransferase 3 (EXTL3) receptor and induces cell growth via signal transduction through JNK and cyclin D1. Intracellular Reg1, however, can inhibit cell growth by direct interaction with MKP-1, inducing a pathway other than mitogenesis. The cyclin D1 gene expression appears to be essentially regulated at the transcription level and the transcriptional activation occurs in a cell type and mitotic stimulation specific manner.[73] The growth of pancreatic β-cells is determined by the number of β-cells entering the cell cycle rather than by changes in the rate of the cycle. Reg, an autocrine/paracrine pancreatic β-cell regeneration factor, appears to stimulate the cell cycle progression through its receptor EXTL-3 (fig.5).[74] Progression from the G1 to S phase of the cell cycle requires the activation of cyclin-dependent kinase (CDK) 4, and the CDK4 activation is controlled by the complex formation with its catalytic partner, cyclin D1. The expression of the cyclin D1 is controlled largely and perhaps entirely by extracellular signals. We have mentioned that Reg activates the cyclin D1 promoter for the cell cycle progression and even Reg receptor overexpression also activates ATF-2 and cyclin D1 promoter in a ligand-independent fashion[68], suggesting that oligomerization of Reg receptor can activate intracellular signaling events like Sky, MET, and CD30 receptors. [75] It has been reported that disruption of the CDK4 gene results in the development of insulin-deficient diabetes due to a reduction in the number of pancreatic β-cells, and that the expression of a mutant CDK4, which escapes from the inhibitory regulation of CDK4, causing islets to become hyperplastic. [76] Thus, evidence in this review suggests that Reg seems to have functions, including promoting tissue

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regeneration, proliferation, and resistance to apoptosis, resulting in relatively worse clinicopathological features. Reg proteins are expressed in colorectal adenoma and intestinal metaplasia of the stomach, diabetes and pancreatitis and is considered to be a good potential marker for gastrointestinal tumors. Reg activates the EGFR/Akt/AP-1 signaling pathway in colon cancer cells, increases cell proliferation, angiogenesis, and metastasis, and reduces apoptosis. Reducing endogenous Reg expression or blocking downstream signaling may be a feasible therapeutic strategy. Further investigations are still needed to confirm these observations and find more anti-cancer agents targeting the Reg/EGFR/Akt/AP-1 signaling pathway.

Figure 5. Proposed Reg1-receptor system for ß-cell replication (Adopted from[3]). Reg1 protein can be induced by inflammatory stimuli (synergistic IL-6 and glucocorticoids) in ß-cells and acinar cells. It acts as an autocrine/paracrine growth factor on ß-cells via the Reg receptor. DNA replication/cell cycle progression in ß-cells occurs via cyclins, and ß-cell replication is achieved. REFERENCES 1. Hartupee, J.C., et al., Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta, 2001; 1518(3): 287-93. 2. Zhang, Y.W., L.S. Ding, and M.D. Lai, Reg gene family and human diseases. World J Gastroenterol, 2003: 9(12): 2635-41.

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