PT  - JOURNAL ARTICLE
AU  - Nazira Özgen
AU  - Jianfen Guo
AU  - Zoya Gertsberg
AU  - Peter Danilo, Jr
AU  - Michael R. Rosen
AU  - Susan F. Steinberg
TI  - Reactive Oxygen Species Decrease cAMP Response Element Binding Protein Expression in Cardiomyocytes via a Protein Kinase D1-Dependent Mechanism That Does Not Require Ser<sup>133</sup> Phosphorylation
AID  - 10.1124/mol.109.056473
DP  - 2009 Oct 01
TA  - Molecular Pharmacology
PG  - 896--902
VI  - 76
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/76/4/896.short
4100  - http://molpharm.aspetjournals.org/content/76/4/896.full
SO  - Mol Pharmacol2009 Oct 01; 76
AB  - 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 Ser133 in cardiomyocytes. Although CREB-Ser133 phosphorylation typically mediates cAMP-dependent increases in CREB target gene expression, the H2O2-dependent increase in CREB-Ser133 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-Ser133 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. © 2009 The American Society for Pharmacology and Experimental Therapeutics