Figure 10.

Cytokine-mediated regulation of the iNOS gene occurs via a coactivator switching mechanism. A, The iNOS gene is silent in pancreatic β-cells in the absence of IL-1β and IFN-γ. RelA/p65 is held in the cytoplasm by regulatory proteins, such as IκBα, whereas the coregulator molecule CBP associates with the transcriptionally inactive iNOS gene promoter in the absence of cytokines. B, Upon β-cell exposure to IL-1β, the IκBα protein is subject to phosphorylation-induced degradation; p65 enters the nucleus and binds κB elements with its heterodimer partner p50. Signaling through the IL-1 receptor (IL-1R) also increases occupancy of Ser727-phosphorylated STAT1 at GAS elements within the iNOS gene promoter. IFN-γ, through JAK-STAT signaling mechanisms, promotes Tyr701 phosphorylation of STAT1, which amplifies the cellular response to IL-1β. These signaling events induce removal of CBP from the iNOS promoter concomitant with the arrival of the coactivators p300 and CARM1.The marked increase in iNOS transcript leads to increased iNOS protein abundance. iNOS catalyzes the production of nitric oxide (NO^•) and citrulline using arginine as a substrate. NO^• accumulation in pancreatic β-cells is linked to losses in insulin secretion and cellular viability.