title: FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide.
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.
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Hughes
authors.affiliation: the Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294, and.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.affiliation: the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Hansen
authors.affiliation: the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: jcorbett@mcw.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins; D000071161:Forkhead Box Protein O1
chemical_list: D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D018797:Cell Cycle Proteins; D045462:Endothelium-Dependent Relaxing Factors; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D009687:Nuclear Proteins; D012333:RNA, Messenger; D056564:Sirtuin 1; C533952:Bbc3 protein, rat; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C505410:Casp3 protein, rat; C488368:Sirt1 protein, rat