Cyclic AMP response element-binding protein mediates reactive oxygen species-induced c-fos expression.
Although the cyclic AMP response element-binding protein (CREB) plays an important role in the survival of neuronal cells and T lymphocytes, the role of CREB in vascular smooth muscle cells (VSMCs) is incompletely characterized. We examined the role of CREB in VSMCs stimulated with reactive oxygen species. Activation of CREB was examined by Western blot analysis with an antibody that specifically recognizes phosphorylation at serine 133 of CREB, which is a critical marker of activation. Hydrogen peroxide (H2O2) time-dependently induced phosphorylation of CREB, with a peak at 15 minutes. The H2O2-induced phosphorylation of CREB was partially blocked by inhibition of either extracellular signal-regulated protein kinase kinase by PD98059 or of p38 mitogen-activated protein kinase (MAPK) by SB203580. AG1478, an epidermal growth factor receptor (EGFR) inhibitor, suppressed the H2O2-induced phosphorylation of CREB and tyrosine phosphorylation of EGFR. Overexpression of the dominant-negative form of CREB by an adenovirus vector suppressed H2O2-induced c-fos expression. These findings suggest that H2O2 induces CREB phosphorylation through EGFR transactivation and mitogen-activated protein kinase pathways. CREB might be a novel redox-sensitive transcription factor involved in the regulation of VSMC gene expression.
Ichiki
Toshihiro
T
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan. ichiki@cardiol.med.kyushu-u.ac.jp
Tokunou
Tomotake
T
Fukuyama
Kae
K
Iino
Naoko
N
Masuda
Satoko
S
Takeshita
Akira
A
D000828:Animal Population Groups; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020218:Response Elements; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation
D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D012694:Serine; D006861:Hydrogen Peroxide