tailieunhanh - Báo cáo khoa học: Double-stranded RNA-dependent protein kinase (PKR) is downregulated by phorbol ester

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 infec-tions, cancer and immune dysfunction. | iFEBS Journal Double-stranded RNA-dependent protein kinase PKR is downregulated by phorbol ester Yan Zhou1 Barbara I. Chase1 Mark Whitmore2 Bryan R. G. Williams2 and Aimin Zhou1 2 1 Department of Chemistry Cleveland State University OH USA 2 Department of Cancer Biology Lerner Research Institute The Cleveland Clinic Foundation OH USA Keywords interferon PKC PKR poly I C proteasome Correspondence A. Zhou ClinicalChemistry Program Department of Chemistry SI 424 Cleveland State University Cleveland OH 44115 USA Fax 1 216 687 9298 Tel 1 216 687 2416 E-mail Received 7 October 2004 revised 22 December 2004 accepted 18 January 2005 doi 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 .

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