Reactive oxygen species decrease cAMP response element binding protein expression in cardiomyocytes via a protein kinase D1-dependent mechanism that does not require Ser133 phosphorylation.
Reactive oxygen species (ROS) exert pleiotropic effects on a wide array of signaling proteins that regulate cellular growth and apoptosis. This study shows that long-term treatment with a low concentration of H2O2 leads to the activation of signaling pathways involving extracellular signal-regulated kinase, ribosomal protein S6 kinase, and protein kinase D (PKD) that increase cAMP binding response element protein (CREB) phosphorylation at Ser(133) in cardiomyocytes. Although CREB-Ser(133) phosphorylation typically mediates cAMP-dependent increases in CREB target gene expression, the H2O2-dependent increase in CREB-Ser(133) phosphorylation is accompanied by a decrease in CREB protein abundance and no change in Cre-luciferase reporter activity. Mutagenesis studies indicate that H2O2 decreases CREB protein abundance via a mechanism that does not require CREB-Ser(133) phosphorylation. Rather, the H2O2-dependent decrease in CREB protein is prevented by the proteasome inhibitor lactacystin, by inhibitors of mitogen-activated protein kinase kinase or protein kinase C activity, or by adenoviral-mediated delivery of a small interfering RNA that decreases PKD1 expression. A PKD1-dependent mechanism that links oxidative stress to decreased CREB protein abundance is predicted to contribute to the pathogenesis of heart failure by influencing cardiac growth and apoptosis responses.
Ozgen
Nazira
N
Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Guo
Jianfen
J
Gertsberg
Zoya
Z
Danilo
Peter
P
Rosen
Michael R
MR
Steinberg
Susan F
SF
D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D017382:Reactive Oxygen Species; D012694:Serine; D006861:Hydrogen Peroxide; D011494:Protein Kinases; C089212:protein kinase D; D011493:Protein Kinase C