FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction.
Diabetes causes pancreatic beta cell failure through hyperglycemia-induced oxidative stress, or "glucose toxicity." We show that the forkhead protein FoxO1 protects beta cells against oxidative stress by forming a complex with the promyelocytic leukemia protein Pml and the NAD-dependent deacetylase Sirt1 to activate expression of NeuroD and MafA, two Insulin2 (Ins2) gene transcription factors. Using acetylation-defective and acetylation-mimicking mutants, we demonstrate that acetylation targets FoxO1 to Pml and prevents ubiquitin-dependent degradation. We show that hyperglycemia suppresses MafA expression in vivo and that MafA inhibition can be prevented by transgenic expression of constitutively nuclear FoxO1 in beta cells. The findings provide a mechanism linking glucose- and growth factor receptor-activated pathways to protect beta cells against oxidative damage via FoxO proteins.
Kitamura
Yukari Ido
YI
Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032, USA.
Kitamura
Tadahiro
T
Kruse
Jan-Philipp
JP
Raum
Jeffrey C
JC
Stein
Roland
R
Gu
Wei
W
Accili
Domenico
D
D000107:Acetylation; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051473:Maf Transcription Factors, Large; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006861:Hydrogen Peroxide; D008156:Luciferases; D051473:Maf Transcription Factors, Large; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D056564:Sirtuin 1; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D001616:beta-Galactosidase; C467200:Foxo1 protein, mouse; C485160:Mafa protein, mouse; C513293:Pml protein, mouse; C093564:Neurogenic differentiation factor 1; C470545:Sirt1 protein, mouse