Document Type
Article
Publication Date
4-1-2005
Publication Title
The FEBS Journal
Abstract
The double-stranded RNA-dependent protein kinase (PKR) is one of the key mediators of interferon (IFN) action against certain viruses. PKR also plays an important role in signal transduction and immunomodulation. Understanding the regulation of PKR activity is important for the use of PKR as a tool to discover and develop novel therapeutics for viral infections, cancer and immune dysfunction. We found that phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), decreased the level of autophosphorylated PKR in a dose- and time-dependent manner in IFN-treated mouse fibroblast cells. Polyinosinic–polycytidylic acid (poly I:C) treatment enhanced the activity of PKR induced by IFN, but did not overcome the PMA-induced reduction of PKR autophosphorylation. Western blot analysis with a monoclonal antibody to mouse PKR revealed that the decrease of PKR autophosphorylation in cells by PMA was a result of PKR protein degradation. Selective PKC inhibitors blocked the degradation of PKR stimulated by PMA, indicating that PKC activity was required for the effect. Furthermore, we also found that proteasome inhibitors prevented PMA-induced down regulation of PKR, indicating that an active proteasome is required. Our results identify a novel mechanism for the post-translational regulation of PKR.
Recommended Citation
Zhou, Yan; Chase, Barbara I.; Whitmore, Mark; Williams, Bryan R.G.; and Zhou, Aimin, "Double-Stranded RNA-Dependent Protein Kinase (PKR) is Downregulated by Phorbol Ester" (2005). Chemistry Faculty Publications. 385.
https://engagedscholarship.csuohio.edu/scichem_facpub/385
DOI
10.1111/j.1742-4658.2005.04572.x
Version
Postprint
Publisher's Statement
This is the accepted version of the following article: Zhou, Y.; Chase, B. I.; Whitmore, M.; Williams, B. R. G.; Zhou, A. Double-stranded RNA-dependent protein kinase (PKR) is downregulated by phorbol ester. FEBS Journal 2005, 272, 1568-1576.which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2005.04572.x/abstract
Volume
272
Issue
7
Comments
This work was supported by the Start-Up Package Fund from Cleveland State University to A.Z. and in part by NIH grant AI34039 to B.R.G.W. We thank Robert H. Silverman (Cleveland Clinic Foundation) and Bret A. Hassel (University Maryland Medical School) for critical reading of the manuscript.