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FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction.
Cell Metab. 2005 Sep; 2(3):153-63.CM

Abstract

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.

Authors+Show Affiliations

Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16154098

Citation

Kitamura, Yukari Ido, et al. "FoxO1 Protects Against Pancreatic Beta Cell Failure Through NeuroD and MafA Induction." Cell Metabolism, vol. 2, no. 3, 2005, pp. 153-63.
Kitamura YI, Kitamura T, Kruse JP, et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab. 2005;2(3):153-63.
Kitamura, Y. I., Kitamura, T., Kruse, J. P., Raum, J. C., Stein, R., Gu, W., & Accili, D. (2005). FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metabolism, 2(3), 153-63.
Kitamura YI, et al. FoxO1 Protects Against Pancreatic Beta Cell Failure Through NeuroD and MafA Induction. Cell Metab. 2005;2(3):153-63. PubMed PMID: 16154098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. AU - Kitamura,Yukari Ido, AU - Kitamura,Tadahiro, AU - Kruse,Jan-Philipp, AU - Raum,Jeffrey C, AU - Stein,Roland, AU - Gu,Wei, AU - Accili,Domenico, PY - 2004/12/13/received PY - 2005/03/29/revised PY - 2005/08/12/accepted PY - 2005/9/13/pubmed PY - 2005/11/9/medline PY - 2005/9/13/entrez SP - 153 EP - 63 JF - Cell metabolism JO - Cell Metab. VL - 2 IS - 3 N2 - 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. SN - 1550-4131 UR - https://www.unboundmedicine.com/medline/citation/16154098/FoxO1_protects_against_pancreatic_beta_cell_failure_through_NeuroD_and_MafA_induction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1550-4131(05)00232-9 DB - PRIME DP - Unbound Medicine ER -