The AP-1 site is essential for the promoter activity of NOX1/NADPH oxidase, a vascular superoxide-producing enzyme: Possible involvement of the ERK1/2-JunB pathway

Biochem Biophys Res Commun. 2008 Sep 19;374(2):351-5. doi: 10.1016/j.bbrc.2008.07.027. Epub 2008 Jul 16.


NADPH oxidase is a major source of the superoxide produced in cardiovascular tissues. The expression of NOX1, a catalytic subunit of NADPH oxidase, is induced by various vasoactive factors, including angiotensin II, prostaglandin (PG) F(2alpha), and platelet-derived growth factor (PDGF). It was reported previously that the inducible expression of NOX1 is governed by the activating transcription factor-1 (ATF-1)-myocyte enhancer factor 2B (MEF2B) cascade downstream of phosphoinositide 3 (PI3) kinase. It was also reported that extracellular signal-regulated kinase (ERK) 1/2 is involved in the expression of NOX1. To further clarify the factors involved in NOX1 induction downstream of ERK1/2, the promoter region of the NOX1 gene was analyzed. A consensus activator protein-1 (AP-1) site was found at -98/-92 in the 5'-flanking region of the rat NOX1 gene. The introduction of mutations at this site abolished PGF(2alpha)-induced transcriptional activation in a luciferase assay. Electrophoresis mobility shift assays demonstrated that PGF(2alpha) and PDGF augmented the binding of JunB to this sequence. PD98059, an inhibitor of MAPK/ERK kinase, suppressed the expression of JunB induced by PGF(2alpha) or PDGF. These results suggest that the ERK1/2-JunB pathway is a key regulator of the inducible expression of the NOX1 gene in vascular smooth muscle cells.

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Consensus Sequence
  • Dinoprost / pharmacology
  • Gene Expression Regulation, Enzymologic*
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Mutation
  • NADH, NADPH Oxidoreductases / genetics*
  • NADPH Oxidase 1
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Superoxides / metabolism
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation*


  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Superoxides
  • Dinoprost
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NOX1 protein, rat
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3