Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice

Aida, Kaoru; Kobayashi, Tetsuro; Takeshita, Akira; Jimbo, Erika; Nishida, Yoriko; Yagihashi, Soroku; Hosoi, M.; Fukui, Tetsuya; Sugawara, Akira; Takasawa, Shin

doi:10.1016/j.bbrc.2018.06.103

Cited by 15 publications

(8 citation statements)

References 15 publications

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“…In contrast, REG1A was overexpressed in ATLANTIS under diabetes (Aida et al, 2014). Furthermore, REG1 was overexpressed in ATLANTIS of Reg1 –/– mice vs. their wildtype counterparts after encephalomyocarditis (EMC) virus infection characterized by β-cell damage and inflammation (Aida et al, 2018). This indicates that REG proteins are crucial in beta cell regeneration in this context.…”

Section: Reg Protein Expression Patterns and Pathophysiologymentioning

confidence: 99%

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

Chen

Downing

Tzanakakis

2019

Front. Cell Dev. Biol.

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Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.

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Section: Reg Protein Expression Patterns and Pathophysiologymentioning

confidence: 99%

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

Chen

Downing

Tzanakakis

2019

Front. Cell Dev. Biol.

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“…In the mouse genome, all the Reg family genes, except for Reg IV , (i.e., Reg I , Reg II , Reg IIIα , Reg IIIβ , Reg IIIγ , and Reg IIIδ ) have been mapped to a contiguous 75 kbp region of chromosome 6C [ 51 ], whereas Reg IV has been mapped on chromosome 3. Type I (and Type II) Reg proteins are expressed in regenerating islets [ 39 , 52 ] and involved in β-cell regeneration [ 3 , 40 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. It has been suggested that Reg family proteins are involved in cellular proliferation in exocrine pancreatic cells [ 62 , 63 ], gastrointestinal cells [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ], hepatic cells [ 76 , 77 , 78 , 79 , 80 ], salivary ductal cells [ 81 , 82 , 83 ], bone and muscle cells [ 84 , 85 ], neuronal cells [ 86 ], and cardiovascular cells [ 30 , 32 , 87 , 88 ].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes

Takasawa

Itaya‐Hironaka²,

Makino³

et al. 2022

IJMS

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Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and is a risk factor for cardiovascular disease (CVD) and insulin resistance/Type 2 diabetes. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes to experimental IH or normoxia for 24 h to analyze the mRNA expression of several cardiomyokines. We found that the mRNA levels of regenerating gene IV (Reg IV) and hepatocyte growth factor (Hgf) in H9c2 and P19.CL6 cardiomyocytes were significantly increased by IH, whereas the promoter activities of the genes were not increased. A target mRNA search of microRNA (miR)s revealed that rat and mouse mRNAs have a potential target sequence for miR-499. The miR-499 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-499 mimic and non-specific control RNA (miR-499 mimic NC) were introduced into P19.CL6 cells, and the IH-induced upregulation of the genes was abolished by introduction of the miR-499 mimic, but not by the miR-499 mimic NC. These results indicate that IH stress downregulates the miR-499 in cardiomyocytes, resulting in increased levels of Reg IV and Hgf mRNAs, leading to the protection of cardiomyocytes in SAS patients.

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“…Delayed development of diabetes and larger islet volume are observed in the offspring of NOD mice crossed with transgenic mice overexpressing Reg1 from an insulin promoter (Ins-Reg) (44). After damage due to encephalomyocarditis virus infection, the islets of Reg1 Ϫ/Ϫ mice exhibit BrdU labeling compared with those of wild-type mice (2). Moreover, diabetic NOD mice exposed to human REG1A display a greater ␤-cell mass than control animals (20).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-7 directly targets Reg1 in pancreatic cells

Downing

Zhang

Chen

et al. 2019

American Journal of Physiology-Cell Physiology

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Regenerating islet-derived (Reg) proteins, which were first discovered in the pancreas, are associated with increased proliferation, prevention of apoptosis, and enhanced differentiation in normal and disease states, but very little is known about the regulation of their expression. We hypothesized that Reg expression is influenced by microRNAs. Bioinformatic analysis predicted Reg1 to be a target of microRNA-7 (miR-7), which influences pancreatic β-cell function. To this end, we investigated the effects of miR-7 on Reg1 expression in pancreatic acinar and islet β-cells. High levels of Reg1 were noted by immunostaining and Western blotting in acinar cells in contrast to islet cells. A reciprocal expression pattern was observed for miR-7. Overexpression of miR-7 resulted in Reg1 mRNA suppression and reduction of secreted Reg1 protein. Conversely, miR-7 knockdown led to increases in Reg1. Targeting of Reg1 by miR-7 was confirmed via luciferase activity assays. In contrast, miR-7 did not directly repress the human ortholog of Reg1 REG1A as well as REG1B indicating species differences in the regulation of Reg expression. This is the first account of microRNA modulation of any Reg member warranting studies to fill gaps in our knowledge of Reg protein biology, particularly in disease contexts.

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Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice

Cited by 15 publications

References 15 publications

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes

MicroRNA-7 directly targets Reg1 in pancreatic cells

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