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- W1448734275 abstract "AACR Annual Meeting-- Apr 18-22, 2009; Denver, COThe eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in various types of human cancers in relation to cellular transformation, tumorigenesis, and metastatic progression. Protein phosphatase 2A (PP2A) is known to function as a tumor suppressor. It is known that Mnks can phosphorylate eIF4E at serine 209 (S209). However, little is known about the regulation of eIF4E phosphorylation by PP2A and the biological function of its phosphorylation on the activity of the translation initiation complex eIF4F. In this study, we used both the PP2A specific inhibitor okadaic acid (OA) and small interfering RNA (siRNA) to demonstrate the role of PP2A in regulation of eIF4E phosphorylation. Inhibition of PP2A using either OA or PP2A siRNA strongly increased eIF4E phosphorylaiton at S209. In the presence of the Mnk inhibitor [CGP57380][1] or deficiency of Mnk genes, eIF4E phosphorylation by OA or PP2A siRNA was abolished, indicating the involvement of Mnks in PP2A-mediated regulation of eIF4E phosphorylation. Through immunoprecipitatiion of PP2A, we could detect phospho-Mnk1 in the precipitated complex by Western blotting, suggesting that PP2A physically interacts with Mnk1. Moreover, m7-GTP pull-down assays detected increased levels of eIF4G and phospho-eIF4E in the precipitated complex from PP2A siRNA-transfected cells compared to those from control siRNA-transfected cells. Accordingly, PP2A knockdown increased the expression of c-Myc, a protein subjected to regulation by a cap-dependent translation mechanism. These data collectively suggest that increased eIF4E phosphorylation by inhibition of PP2A triggers an enhanced assembly of the translation initiation complex eIF4F and thereby facilitates cap-dependent translation in human cancer cells. Taken together, we conclude that PP2A negatively regulates eIF4E phosphorylation, likely though inhibition of Mnk activity, and eIF4F activity or cap-dependent translation. Thus, our findings suggest a novel mechanism by which PP2A exerts its tumor suppressing function through inhibition of eIF4E-mediated cap-dependent protein translation. (Supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award and NIH/NCI RO1 CA118450-01; SY Sun, and FR Khuri are Georgia Cancer Coalition Distinguished Cancer Scholars)Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5348. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=CGP57380&atom=%2Fcanres%2F69%2F9_Supplement%2F5348.atom" @default.
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- W1448734275 date "2009-05-01" @default.
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- W1448734275 title "Abstract #5348: Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E (eIF4E) phosphorylation and eIF4F activity" @default.
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