Pancreatic Reg I Binds MKP-1 and Regulates Cyclin D in Pancreatic-Derived Cells

Mueller, Cathy M.; Zhang, Hong; Zenilman, Michael E.

doi:10.1016/j.jss.2008.03.047

Cited by 23 publications

(24 citation statements)

References 26 publications

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“…In addition, we did not observe a difference in the growth of cells exposed to Reg1 compared to that of cells infected with AdReg1GFP (ie, higher endogenous levels of Reg1) unlike previous fi ndings [ 42 ]. Similarly, there was no noticeable difference in the number of cells A previous report [ 42 ] indicated that pancreatic ductal and β-cells exposed to exogenous Reg1 showed a mitogenic response whereas cells transfected with a Reg1 expression vector (thereby having elevated intracellular Reg1 protein) showed inhibited growth. Thus, mESCs infected with recombinant adenoviruses carrying the mouse Reg1 and GFP genes (AdReg1GFP) or only the GFP (AdGFP; control) gene were also included in this series of experiments.…”

Section: Reg1 and Mesc Differentiationcontrasting

confidence: 99%

“…Based on our fi ndings, we consider in the absence of LIF or Reg1 was overexpressed by infecting cells with a recombinant adenovirus carrying the Reg1 gene (AdReg1GFP). It was reported previously that Reg1 can inhibit the growth of pancreatic cells when overexpressed within cells or in very high extracellular levels (over 100 nM) [ 42 ]. In our study, the concentrations of exogenous Reg1 and expressed Reg1 after infection with AdReg1GFP were well below 100 nM.…”

Section: Discussionsupporting

confidence: 53%

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Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

Jing

Kehoe

Tzanakakis

2010

Stem Cells and Development

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Regenerating islet (Reg) proteins are involved in the proliferation and differentiation of diverse cell types. However, whether embryonic stem cells (ESCs) express Reg genes and their corresponding proteins remains unknown. In this study, we probed the expression of Reg family members by mouse ESCs (mESCs). Mouse Reg1 and Reg3γ were detected in undifferentiated stem cells. Furthermore, we tested if gastrin-an inducer of Reg1 expression in committed cells-up-regulates the Reg1 gene in mESCs. Gastrin did not affect the expression of Reg1 either in self-renewing mESCs or under conditions permitting their differentiation. Moreover, overexpression of Reg genes found in various forms of cancer has been linked to dysregulated activation of the canonical Wnt/β-catenin cascade. Given the important roles of Wnt signaling in stem cells, we investigated if activation of Wnt alters the expression of Reg genes in mESCs. Wnt activation led to an increase in Reg1 gene expression with a concomitant increase in the amount of secreted Reg1 protein. Finally, the expression pattern of genes indicative of differentiation was examined in mESCs that were either exposed to soluble Reg1 or overexpressed the Reg1 gene. This is the fi rst account of expression of Reg family members by ESCs. Our results show that the canonical Wnt cascade affects Reg expression and warrants further studies into the potential roles of Reg proteins in stem cell physiology.

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Section: Reg1 and Mesc Differentiationcontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 53%

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

Jing

Kehoe

Tzanakakis

2010

Stem Cells and Development

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“…But, reg I can have an intracellular effect through a reg I-receptor-independent pathway. We recently showed that reg I directly binds to MKP-1 [21] and activate signal transduction pathways. High intracellular levels of reg I bind with MKP-1, and through subsequent modulation of the JNK and cyclin D1 pathways, regI-MKP-1 complexes can affect differentiation[21].…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Regenerating Gene I and Acinar Cell Differentiation

2009

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Objectives Pancreatic reg I has been implicated in cellular differentiation. Acinar cells can transdifferentiate into other pancreatic-derived cells, and we postulated that changes in intracellular levels of reg I would affect the state of differentiation. Methods We transfected AR42J cells with a plasmid containing the entire coding sequence of reg I, and isolated clones with cDNA in sense (SS) or antisense (AS) orientation. Levels of mRNA and protein expression were examined by Western blotting and Real Time-PCR. Results Expression of reg I was confirmed in sense or antisense clones. AR42J transfected with SS demonstrated more acinar-like phenotype while those transfected with AS showed a less differentiated state. Specifically, amylase mRNA and protein levels increased in SS cells while AS cells showed increased PDX-1 and insulin mRNAs and cytokeratin protein. Conversely, cytokeratin and PDX-1 were depressed in SS cells. Conclusions These data demonstrate that in acinar cells, reg I over-expression is linked to acinar cell differentiation, while inhibition of reg I leads to beta-cell and possibly ductal phenotype. Reg I expression in acinar cells is important in maintaining pancreatic cell lineage, and when decreased, cells can de-differentiate and move towards becoming other pancreatic cells.

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“…Furthermore, we also observed a clear effect on REG1A and REG1B, which are acinar cell-derived proliferation factors shown to be involved in β-cell proliferation. 54 Several members of the Reg gene family have already been identified as being induced by GLP-1, 55 although this is the first report in human islets. However, overexpression of REG1 has also been associated with accelerated diabetes in NOD mice 56 and has been shown to inhibit β-cell growth and possibly induces apoptosis.…”

Section: Journal Of Proteome Researchmentioning

confidence: 90%

Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

Rondas¹,

Bugliani

D’Hertog³

et al. 2013

J. Proteome Res.

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Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.

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Pancreatic Reg I Binds MKP-1 and Regulates Cyclin D in Pancreatic-Derived Cells

Abstract: Background-The pancreatic regenerating (reg I) gene and its protein product are derived from acinar cells, and are mitogenic to β-and ductal cells. We studied the mechanism of this mitogenic response.

Cited by 23 publications

References 26 publications

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

Pancreatic Regenerating Gene I and Acinar Cell Differentiation

Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

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