HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase.
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(1) 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.
Berasi
Stephen P
SP
Department of Biochemistry, Tufts University School of Medicine, School of Nutrition, Boston, Massachusetts 02111, USA.
Xiu
Mei
M
Yee
Amy S
AS
Paulson
K Eric
KE
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
C486328:HBP1 protein, human; C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013481:Superoxides; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1