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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-d, 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 dominantnegative expression) of PKC-d confirm a role for this PKC isoform in EGF-dependent COX-2 induction. Overexpression of a functional PKC-d enhanced COX-2 expression indicating that PKC-d 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-d by EGF while inhibition of PKC-d had no discernible effects on p38-MAPK activation. Finally, EGF stimulation promotes physical interactions between PKC-d and Sp1 resulting in phosphorylation and nuclear localization of this transcription factor. These data provide the first evidence that PKC-d is a critical link between p38-MAPK and Sp1-dependent COX-2 expression in human glioma cells.

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