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Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-δ

Oncogene volume 28, pages 1410–1420 (2009)Cite this article

Abstract

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

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Acknowledgements

This study was supported, in part, by a grant to H-K Shu from the Childhood Brain Tumor Foundation. We thank Dr Jiahuai Han for providing mammalian expression plasmids-containing MKK3 and MKK6 and Dr Jae-Won Soh for providing mammalian expression plasmids-containing PKC-δ variants.

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  1. Department of Radiation Oncology, Emory University, Atlanta, GA, USA

    K Xu, C-M Chang, H Gao & H-K G Shu

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Correspondence to H-K G Shu.

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Xu, K., Chang, CM., Gao, H. et al. Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-δ. Oncogene 28, 1410–1420 (2009). https://doi.org/10.1038/onc.2008.500

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