Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-delta.
Earlier, we showed that epidermal growth factor receptor (EGFR) signaling in human glioma cells increased cyclooxygenase-2 (COX-2) expression through p38-mitogen-activated protein kinase (MAPK)-dependent activation of the Sp family of transcription factors. Further mechanistic details of EGFR-dependent induction of COX-2 expression in glioma cells remained elusive. Protein kinase Cs (PKCs) comprise a family of serine-threonine kinases that are major mediators of signaling from receptor tyrosine kinases. Here, we report that PKC-delta, a novel PKC isoform, plays a role in EGF-dependent COX-2 induction in human glioma cells. Pharmacological inhibition and genetic silencing (through siRNA or dominant-negative expression) of PKC-delta confirm a role for this PKC isoform in EGF-dependent COX-2 induction. Overexpression of a functional PKC-delta enhanced COX-2 expression indicating that PKC-delta is not only necessary but also sufficient to regulate COX-2 levels. Inhibition of p38-MAPK pharmacologically or with siRNA further shows that p38-MAPK is required for activation of PKC-delta by EGF while inhibition of PKC-delta had no discernible effects on p38-MAPK activation. Finally, EGF stimulation promotes physical interactions between PKC-delta and Sp1 resulting in phosphorylation and nuclear localization of this transcription factor. These data provide the first evidence that PKC-delta is a critical link between p38-MAPK and Sp1-dependent COX-2 expression in human glioma cells.
Xu
K
K
Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.
Chang
C-M
CM
Gao
H
H
Shu
H-K G
HK
D021581:Active Transport, Cell Nucleus; D001932:Brain Neoplasms / Q000201:enzymology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005910:Glioma / Q000201:enzymology*; D006801:Humans; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000502:physiology*; D051703:Sp Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D051703:Sp Transcription Factors; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases