PAP IB, a new member of the Reg gene family: Cloning, expression, structural properties, and evolution by gene duplication

Laurine, Emmanuelle; Manival, Xavier; Montgelard, Claudine; Bideau, Chantal; Bergé-Lefranc, Jean-Louis; Erard, Marie; Verdier, Jean‐Michel

doi:10.1016/j.bbaexp.2005.01.011

Cited by 22 publications

(15 citation statements)

References 53 publications

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“…Among them, Reg1 is clearly linked to islet cell proliferation/regeneration [99,100]; islet neogenesis-associated protein (INGAP; Reg3d) promotes b-cell regeneration from pancreatic ductal cells [101,102]. Consequently, five new members of the family (Reg2, 3a, 3b, 3c, and Reg4) have been discovered [103][104][105][106]; three of them exhibited elevated expression in the pancreas of our PID mice. In contrast, the responses of Reg1 and INGAP in our system were only marginal.…”

Section: Liver-and Pancreatic-specific Igf-i Gene Deficiency Increasementioning

confidence: 92%

Does IGF-I stimulate pancreatic islet cell growth?

Liu

2007

Cell Biochem Biophys

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Both IGF-I and its receptor (IGF-IR) are specifically expressed in various cell types of the endocrine pancreas. IGF-I has long been considered a growth factor for islet cells as it induces DNA synthesis in a glucose-dependent manner, prevents Fas-mediated autoimmune beta-cell destruction and delays onset of diabetes in non-obese diabetic (NOD) mice. Islet-specific IGF-I overexpression promotes islet cell regeneration in diabetic mice. However, in the last few years, results from most gene-targeted mice have challenged this view. For instance, combined inactivation of insulin receptor and IGF-IR or IGF-I and IGF-II genes in early embryos results in no defect on islet cell development; islet beta-cell-specific inactivation of IGF-IR gene causes no change in beta-cell mass; liver- and pancreatic-specific IGF-I gene deficiency (LID and PID mice) suggests that IGF-I exerts an inhibitory effect on islet cell growth albeit indirectly through controlling growth hormone release or expression of Reg family genes. These results need to be evaluated with potential gene redundancy, model limitations, indirect effects and ligand-receptor cross-activations within the insulin/IGF family. Although IGF-I causes islet beta-cell proliferation and neogenesis directly, what occur in normal physiology, pathophysiology or during development of an organism might be different. Locally produced and systemic IGF-I does not seem to play a positive role in islet cell growth. Rather, it is probably a negative regulator through controlling growth hormone and insulin release, hyperglycemia, or Reg gene expression. These results complicate the perspective of an IGF-I therapy for beta-cell loss.

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Section: Liver-and Pancreatic-specific Igf-i Gene Deficiency Increasementioning

confidence: 92%

Does IGF-I stimulate pancreatic islet cell growth?

Liu

2007

Cell Biochem Biophys

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“…of a large family (2). It was first described as being secreted in pancreatic juice where it may control the growth of calcium carbonate crystals (3)(4)(5).…”

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confidence: 99%

Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

Marchal

François

et al. 2012

Journal of Biological Chemistry

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Background: Reg-1␣ is a small secretory protein overexpressed during the early stages of Alzheimer disease. Results: Secreted Reg-1␣ stimulates axon outgrowth, and this paracrine effect is mediated by its receptor EXTL3. Conclusion: Reg-1␣ emerges as an important actor in brain plasticity and the regenerative process. Significance: Learning how Reg-1␣ regulates the nerve cells is important for understanding its implications in early stages of Alzheimer disease.

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“…Reg family proteins have been known for years; e.g., Reg1 [pancreatic thread protein (PTP), pancreatic stone protein (PSP)] stimulates islet cell proliferation/regeneration (45, 47); islet neogenesis-associated protein [INGAP; INGAP-related peptide (rp) Reg3␦] promotes ␤-cell neogenesis from pancreatic ductal cells (35,38). Consequently, five new members of the family (Reg2, -3␣, -3␤, -3␥, and -4) have been discovered (1,22,27,56); three of them (Reg2, -3␣, and -3␤) exhibited elevated expression in our PID mice. Increased Reg2 and Reg3␤ levels have been reported in human and rodent T1D (4, 13).…”

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confidence: 99%

Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas

Lu¹,

Ponton²,

Okamoto³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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. Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. Am J Physiol Endocrinol Metab 291: E50 -E58, 2006. First published January 31, 2006 doi:10.1152/ajpendo.00596.2005.-We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased ␤-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3␣, and -3␤, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2-to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced ␤-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas and suggested their potential role in ␤-cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and islet neogenesis-associated protein) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D. pancreatic islets; DNA microarray; gene-targeted mice; insulin-like growth factor I INSULIN-LIKE GROWTH FACTOR I (IGF-I) is produced from hepatocytes and many other cells and tissues, including the pancreas (9, 14, 23). Acting through its receptor IGF-IR, which is expressed ubiquitously, IGF-I promotes cell proliferation and growth and inhibits cell apoptosis. In normal growth of the bone, muscle, reproductive systems, and the whole mammalian organisms, IGF-I plays an irreplaceable, essential role (25,33). In cultured cells, IGF-I causes pancreatic islet ␤-cell mitogenesis in a glucose-dependent manner via activation of phosphatidylinositol 3-kinase (PI3K), ERK1/2, and 70-kDa protein S6 kinase (p70 S6K ) (15, 24). Although IGF-I and IGF-IR are normally expressed in both endocrine and exocrine pancreas (8, 9), their in vivo role in islet cell growth has been questioned by the results of most gene-targeted studies. For example, combined inactivation of insulin receptor and IGF-IR genes in early embryos results in a 50% decrease in the size of the exocrine pancreas without affecting the development of endocrine cells (19). Combined ablation of IGF-I and IGF-II genes results in an identical phenotype (19). Moreover, islet ␤-cellspecific inactivation of IGF-IR gene causes no change in ␤-cell mass despite hyperinsulinemia, glucose intoleranc...

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PAP IB, a new member of the Reg gene family: Cloning, expression, structural properties, and evolution by gene duplication

Cited by 22 publications

References 53 publications

Does IGF-I stimulate pancreatic islet cell growth?

Does IGF-I stimulate pancreatic islet cell growth?

Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas

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