title: Trefoil factor 2 promotes cell proliferation in pancreatic β-cells through CXCR-4-mediated ERK1/2 phosphorylation.
abstract: Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Orime
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Togashi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tajima
authors.forename: Hideaki
authors.initials: H
authors.lastname: Inoue
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ito
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sato
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nakamura
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aoki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D002070:Butadienes; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D000071164:Trefoil Factor-2
chemical_list: D002070:Butadienes; D009077:Mucins; D009124:Muscle Proteins; D009570:Nitriles; D010455:Peptides; D019718:Receptors, CXCR4; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3