Transactivation of the EGF receptor and a PI3 kinase–ATF-1 pathway is involved in the upregulation of NOX1, a catalytic subunit of NADPH oxidase

• Published in: FEBS letters 2005-02, Vol.579 (5), p.1301-1305
• Main Authors: Fan, ChunYuan, Katsuyama, Masato, Nishinaka, Toru, Yabe-Nishimura, Chihiro
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 1; Animals; Catalysis; Cell Line; Dinoprost - pharmacology; DNA-Binding Proteins - metabolism; EGF; epidermal growth factor; Epidermal growth factor receptor; ERK; extracellular signal-regulated protein kinase; MAPK; MAPK/ERK kinase; matrix metalloproteinase; Matrix Metalloproteinases - metabolism; MEK; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; MMP; NADH, NADPH Oxidoreductases - genetics; NADH, NADPH Oxidoreductases - metabolism; NADPH oxidase; NADPH Oxidase 1; NOX1; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; phosphoinositide 3; Phosphoinositide 3 kinase; Phosphorylation - drug effects; PI3; prostaglandin; Prostaglandin F2α; Protein Kinase Inhibitors - pharmacology; Protein Subunits - genetics; Protein Subunits - metabolism; Rats; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Up-Regulation
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2005.01.021

We previously reported that hypertrophy of vascular smooth muscle cells caused by prostaglandin (PG) F2α is mediated by the induction of NOX1, a catalytic subunit of NADPH oxidase that generates superoxide. The signal transduction pathway(s) involved in this process, however, remained unresolved. PGF2α enhanced the phosphorylation of the epidermal growth factor (EGF) receptor, and a selective inhibitor of EGF receptor kinase, tyrphostin AG1478, significantly suppressed PGF2α-induced NOX1 expression. AG1478 also blunted the PGF2α-induced phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and Akt. Phosphoinositide 3 (PI3) kinase inhibitors not only reduced PGF2α-induced NOX1 expression, but also suppressed the phosphorylation of ATF-1, a transcription factor previously shown to play a key role in the induction of NOX1. Accordingly, the transactivation of the EGF receptor and the activation of ERK1/2, PI3 kinase, and ATF-1 constitute the signaling pathways involved in the upregulation of NOX1.