Nuclear EGFR Suppresses Ribonuclease Activity of Polynucleotide Phosphorylase through DNAPK-mediated Phosphorylation at Serine 776

ASIA unversity > 醫學暨健康學院 > 生物科技學系 > 期刊論文 > Item 310904400/16948

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Title:	Nuclear EGFR Suppresses Ribonuclease Activity of Polynucleotide Phosphorylase through DNAPK-mediated Phosphorylation at Serine 776
Authors:	余永倫;Yu, Yung-luen;鄒瑞煌;Chou, Ruey-Hwang;Lee HJ,;Chen, CH;洪明奇;Hung, Mien-Chie
Contributors:	生物科技學系
Keywords:	nuclear EGFR;radioresistance;p-PNPase;breast cancer;c-MYC
Date:	2012-09
Issue Date:	2012-11-23 17:18:44 (UTC+8)
Abstract:	Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than two decades. Resistance of cancer to radiotherapy is frequently correlated with elevated EGFR expression, activity, and nuclear translocation. However, the role of nuclear EGFR (nEGFR) in radioresistance of cancers remains elusive. In the current study, we identified a novel nEGFR-associated protein, polynucleotide phosphorylase (PNPase), which possesses 3′ to 5′ exoribonuclease activity toward c-MYC mRNA. Knockdown of PNPase increased radioresistance. Inactivation or knock-down of EGFR enhanced PNPase-mediated c-MYC mRNA degradation in breast cancer cells, and also increased its radiosensitivity. Interestingly, the association of nEGFR with PNPase and DNA-dependent protein kinase (DNAPK) increased significantly in breast cancer cells after exposure to ionizing radiation (IR). We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. The phosphomimetic S776D mutant of PNPase impaired its ribonuclease activity whereas the nonphosphorylatable S776A mutant effectively degraded c-MYC mRNA. Here, we uncovered a novel role of nEGFR in radioresistance, and that is, upon ionizing radiation, nEGFR inactivates the ribonuclease activity of PNPase toward c-MYC mRNA through DNAPK-mediated Ser-776 phosphorylation, leading to increase of c-MYC mRNA, which contributes to radioresistance of cancer cells. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Relation:	JOURNAL OF BIOLOGICAL CHEMISTRY
Appears in Collections:	[生物科技學系] 期刊論文

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