title: NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation.
abstract: In megakaryocytes, the maturation process and oxidative stress response appear to be closely related. It has been suggested that increased oxygen tension and reactive oxygen species (ROS) promote megakaryopoiesis and that the expression of stress-responsive genes responsible for ROS elimination declines during megakaryocytic maturation. NF-E2 p45 is an essential regulator of megakaryopoiesis, whereas Nrf2 is a key activator of stress-responsive genes. Because p45 and Nrf2 have similar DNA-binding specificities, we hypothesized that p45 competes with Nrf2 to repress stress-responsive genes and achieves favorable intracellular conditions to allow ROS to be efficiently used as signaling molecules. We conducted comprehensive gene expression profiling with wild-type and p45-null megakaryocytes and examined the functional relationship between p45 and Nrf2. We found that 2 characteristic gene clusters are defined within p45 target genes: platelet genes and cytoprotective genes. The former are unique targets activated by p45, whereas the latter are common targets of p45 and Nrf2. Further analysis suggested that, as a less efficacious activator, p45 maintains moderate expression of cytoprotective genes through competing with Nrf2 and promotes ROS accumulation. Increased ROS enhanced platelet gene expression. These results suggest that p45 dominates over Nrf2 to enhance megakaryocytic maturation by promoting ROS accumulation.
authors.affiliation: Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. hozumim@m.tains.tohoku.ac.jp
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Momoko
authors.initials: M
authors.lastname: Kimura
authors.forename: Rie
authors.initials: R
authors.lastname: Fujita
authors.forename: Ai
authors.initials: A
authors.lastname: Inoue
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Pan
authors.forename: Mariko
authors.initials: M
authors.lastname: Takayama
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism*; D034061:Thrombopoiesis / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D050984:NF-E2 Transcription Factor, p45 Subunit; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species