Model for p45 and Nrf2-regulated megakaryocytic maturation. (A) In WT megakaryocytes at an immature stage (WT, left panel), Nrf2 seems to make a major contribution to cytoprotective gene regulation, which could promote cell proliferation. In mature megakaryocytes (WT, right panel), p45, as a modest activator, seems to maintain the moderate expression of cytoprotective genes by competing with Nrf2 and to enhance ROS accumulation. Increased ROS cooperates with p45 to promote platelet gene expression. (B) In p45-null cells, platelet genes are dramatically repressed and cytoprotective genes are induced by Nrf2, resulting in the reduction of ROS levels. In Nrf2-null cells, neither gene expressions nor ROS levels are changed. In both cases, proliferation of megakaryocytes is impaired (right panels). In Keap1-null cells, constitutively activated Nrf2 strongly activates cytoprotective genes but not platelet genes. ROS accumulation is inhibited, and proliferation of immature megakaryocytes is promoted (left panel). Solid and broken black arrows indicate explicit and ineffective interaction, respectively.