Ranjan Priya, Anathy Vikas, Burch Peter M, Weirather Kelly, Lambeth J David, Heintz Nicholas H
Department of Pathology and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, 05405, USA.
Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1447-59. doi: 10.1089/ars.2006.8.1447.
NADPH oxidases produce reactive oxygen species (ROS) that serve as co-stimulatory signals for cell proliferation. In mouse lung epithelial cells that express Nox1, Nox2, Nox4, p22(phox), p47(phox), p67(phox), and Noxo1, overexpression of Nox1 delayed cell cycle withdrawal by maintaining AP-1-dependent expression of cyclin D1 in low serum conditions. In cycling cells, the effects of Nox1 were dose dependent: levels of Nox1 that induced 3- to 10-fold increases in ROS promoted phosphorylation of ERK1/2 and expression of cyclin D1, whereas expression of Nox1 with Noxo1 and Noxa1 (or expression of Nox4 alone) that induced substantial increases in intracellular ROS inhibited cyclin D1 and proliferation. Catalase reversed the effects of Nox1 on cyclin D1 and cell proliferation. Diphenylene iodonium, an inhibitor of NADPH oxidase activity, did not affect dosedependent responses of ERK1/2 or Akt to serum, but markedly inhibited the sequential expression of c-Fos and Fra-1 required for induction of cyclin D1 during cell cycle re-entry. These results indicate that Nox1 stimulates cell proliferation in actively cycling cells by reducing the requirement for growth factors to maintain expression of cyclin D1, whereas during cell cycle re-entry, NADPH oxidase activity is required for transcriptional activation of Fos family genes during the immediate early gene response.
NADPH氧化酶产生活性氧（ROS），其作为细胞增殖的共刺激信号。在表达Nox1、Nox2、Nox4、p22（phox）、p47（phox）、p67（phox）和Noxo1的小鼠肺上皮细胞中，Nox1的过表达通过在低血清条件下维持细胞周期蛋白D1的AP-1依赖性表达来延迟细胞周期退出。在循环细胞中，Nox1的作用呈剂量依赖性：诱导ROS增加3至10倍的Nox1水平促进ERK1/2的磷酸化和细胞周期蛋白D1的表达，而与Noxo1和Noxa1一起表达的Nox1（或单独表达Nox4）诱导细胞内ROS大量增加，抑制细胞周期蛋白D1和增殖。过氧化氢酶逆转了Nox1对细胞周期蛋白D1和细胞增殖的影响。二苯基碘鎓，一种NADPH氧化酶活性抑制剂，不影响ERK1/2或Akt对血清的剂量依赖性反应，但显著抑制细胞周期重新进入期间诱导细胞周期蛋白D1所需的c-Fos和Fra-1的顺序表达。这些结果表明，Nox1通过降低维持细胞周期蛋白D1表达所需的生长因子需求来刺激活跃循环细胞中的细胞增殖，而在细胞周期重新进入期间，NADPH氧化酶活性是早期即刻基因反应期间Fos家族基因转录激活所必需的。
