HBP1 repression of the p47phox gene: Cell cycle regulation via the NADPH oxidase
HBP1 repression of the p47phox gene: Cell cycle regulation via the NADPH oxidase
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DOI：
10.1128/mcb.24.7.3011-3024.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Paulson, KE
中科院分区：
文献类型：
--
作者：
Berasi, SP;Xiu, M;Paulson, KE
一些研究已经将NADPH氧化酶产生的活性氧(ROS)与细胞生长控制联系起来。在许多情况下，NADPH氧化酶的激活和随后的ROS的产生是非免疫细胞中生长因子信号和有丝分裂发生所必需的。在这项研究中，我们证明了转录抑制物HBP1(HMG盒包含蛋白1)调控NADPH氧化酶p47Phox调节亚基的基因。HBP1抑制生长调控基因(如N-Myc、c-Myc和细胞周期蛋白D1)，是G期进程的抑制因子。P47Phox基因的启动子在转录起始点的-1243~-1318bp处含有6个串联的高亲和力HBP1DNA结合元件，这是抑制所必需的。此外，HBP1通过序列特异性结合抑制内源性p47Phox基因的表达。随着HBP1的表达和随后p47Phox基因表达的降低，细胞内超氧化物的产生相应减少。利用HBP1的野生型和显性负性突变体，我们证明了HBP1通过NADPH氧化酶抑制超氧化物产生有助于观察到HBP1对细胞周期的抑制。综上所述，这些结果表明HBP1可能通过转录抑制p47Phox基因参与调节NADPH氧化酶依赖的超氧化物的产生。这项研究定义了一种调控细胞内ROS水平的转录机制，并对细胞周期调控具有一定的意义。
Several studies have linked the production of reactive oxygen species (ROS) by the NADPH oxidase to cellular growth control. In many cases, activation of the NADPH oxidase and subsequent ROS generation is required for growth factor signaling and mitogenesis in nonimmune cells. In this study, we demonstrate that the transcriptional repressor HBP1 (HMG box-containing protein 1) regulates the gene for the p47phox regulatory subunit of the NADPH oxidase. HBP1 represses growth regulatory genes (e.g., N-Myc, c-Myc, and cyclin D1) and is an inhibitor of G, progression. The promoter of the p47phox gene contains six tandem high-affinity HBP1 DNA-binding elements at positions -1243 to -1318 bp from the transcriptional start site which were required for repression. Furthermore, HBP1 repressed the expression of the endogenous p47phox gene through sequence- specific binding. With HBP1 expression and the subsequent reduction in p47phox gene expression, intracellular superoxide production was correspondingly reduced. Using both the wild type and a dominant-negative mutant of HBP1, we demonstrated that the repression of superoxide production through the NADPH oxidase contributed to the observed cell cycle inhibition by HBP1. Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene. This study defines a transcriptional mechanism for regulating intracellular ROS levels and has implications in cell cycle regulation.