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.
Highlights
Nitric oxide plays a central role in regulating the response(s) of pancreatic -cells to cytokine treatment
The nitric-oxide synthase (NOS) inhibitor NG-Monomethyl arginine (NMMA) prevents the loss of serine residue 256 (Ser-256) phosphorylation of FoxO1 in response to IL-1
Kitamura et al [41] have shown that nuclear, transcriptionally active FoxO1 is rapidly ubiquitinated and degraded by the proteasome. Consistent with these findings, there is a significant reduction in the levels of total FoxO1 in INS 832/13 cells treated for 24 h with IL-1, and this loss of FoxO1 is prevented by NMMA (Fig. 1A)
Summary
Nitric oxide plays a central role in regulating the response(s) of pancreatic -cells to cytokine treatment. In response to SIRT1 inhibitors, the FoxO1-dependent protective actions of nitric oxide (GADD45␣ 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.
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