title: Nkx6.1-mediated insulin secretion and β-cell proliferation is dependent on upregulation of c-Fos.
abstract: Understanding the molecular pathways that enhance β-cell proliferation, survival, and insulin secretion may be useful to improve treatments for diabetes. Nkx6.1 induces proliferation through the Nr4a nuclear receptors, and improves insulin secretion and survival through the peptide hormone VGF. Here we demonstrate that Nkx6.1-mediated upregulation of Nr4a1, Nr4a3, and VGF is dependent on c-Fos expression. c-Fos overexpression results in activation of Nkx6.1 responsive genes and increases β-cell proliferation, insulin secretion, and cellular survival. c-Fos knockdown impedes Nkx6.1-mediated β-cell proliferation and insulin secretion. These data demonstrate that c-Fos is critical for Nkx6.1-mediated expansion of functional β-cell mass.
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Ray
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Kener
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Bitner
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Wright
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ballard
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Barrett
authors.affiliation: Physiology and Developmental Biology Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Jonathon T
authors.initials: JT
authors.lastname: Hill
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University, Durham, NC, USA.
authors.forename: Larry G
authors.initials: LG
authors.lastname: Moss
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT, USA.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Tessem
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C491327:Nkx6-1 protein, rat; C539820:Nr4a1 protein, rat; C091333:Nr4a3 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016760:Proto-Oncogene Proteins c-fos; C062040:Vgf protein, rat
keywords: Nkx6.1; Nr4a1; Nr4a3; VGF; c-Fos; β-cell