FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide

Katherine J Hughes; Gordon P Meares; Polly A Hansen; John A Corbett

doi:10.1074/jbc.M110.204768

FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide

J Biol Chem. 2011 Mar 11;286(10):8338-8348. doi: 10.1074/jbc.M110.204768. Epub 2011 Jan 1.

Authors

Katherine J Hughes¹, Gordon P Meares², Polly A Hansen³, John A Corbett⁴

Affiliations

¹ From the Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104.
² the Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294, and.
³ the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
⁴ the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: jcorbett@mcw.edu.

Abstract

For many cell types, including pancreatic β-cells, nitric oxide is a mediator of cell death; paradoxically, nitric oxide can also activate pathways that promote the repair of cellular damage. In this report, a role for FoxO1-dependent transcriptional activation and its regulation by SIRT1 in determining the cellular response to nitric oxide is provided. In response to nitric oxide, FoxO1 translocates from the cytoplasm to the nucleus and stimulates the expression of the DNA repair gene GADD45α, resulting in FoxO1-dependent DNA repair. FoxO1-dependent gene expression appears to be regulated by the NAD(+)-dependent deacetylase SIRT1. In response to SIRT1 inhibitors, the FoxO1-dependent protective actions of nitric oxide (GADD45α expression and DNA repair) are attenuated, and FoxO1 activates a proapoptotic program that includes PUMA (p53-up-regulated mediator of apoptosis) mRNA accumulation and caspase-3 cleavage. These findings support primary roles for FoxO1 and SIRT1 in regulating the cellular responses of β-cells to nitric oxide.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Active Transport, Cell Nucleus / drug effects
Animals
Apoptosis / drug effects
Apoptosis / genetics
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Caspase 3 / genetics
Caspase 3 / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line
Cell Nucleus / genetics
Cell Nucleus / metabolism*
DNA Repair*
Endothelium-Dependent Relaxing Factors / metabolism
Endothelium-Dependent Relaxing Factors / pharmacology
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Insulin-Secreting Cells / metabolism*
Male
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Nitric Oxide / metabolism*
Nitric Oxide / pharmacology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Sirtuin 1 / genetics
Sirtuin 1 / metabolism*

Substances

Apoptosis Regulatory Proteins
Bbc3 protein, rat
Cell Cycle Proteins
Endothelium-Dependent Relaxing Factors
Forkhead Transcription Factors
Gadd45a protein, rat
Nerve Tissue Proteins
Nuclear Proteins
RNA, Messenger
Foxo1 protein, rat
Nitric Oxide
Casp3 protein, rat
Caspase 3
Sirt1 protein, rat
Sirtuin 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding