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The PCPH Oncoprotein Antagonizes the Proapoptotic Role of the Mammalian Target of Rapamycin in the Response of Normal Fibroblasts to Ionizing Radiation¹

Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine [O. M. T., S. M-L., S. S., V. N.], and Department of Cell Biology [L. E. D.], Georgetown University Medical Center, Washington, DC 20057-1482

Exposure of normal mouse fibroblasts (MEF3T3) to ionizing radiation (IR) resulted in a dose-dependent increase of mTOR mRNA and protein levels and the shuttling of the mTOR protein from its normal, predominantly mitochondrial location to the cell nucleus. The same IR doses that activated mTOR induced the phosphorylation of p53 on Ser¹⁸ (mouse equivalent to human Ser¹⁵) and the subsequent transcriptional activation of PUMA, a known proapoptotic p53-target gene, and promoted apoptosis involving increased overall caspase activity, caspase-3 activation, cleavage of poly(ADP-ribose) polymerase (PARP) and classic protein kinase C (PKC) isoforms, and DNA fragmentation. The proapoptotic role of mTOR in this process was demonstrated by the fact that rapamycin, a mTOR inhibitor, blocked p53 Ser¹⁸ phosphorylation, the induction of PUMA, and all other apoptosis events. Furthermore, the proapoptotic function of mTOR was also antagonized by the expression in MEF3T3 cells of the PCPH oncoprotein, known to enhance cell survival by causing partial ATP depletion. Tetracyclin (Tet)-regulated expression of oncogenic PCPH, or overexpression of normal PCPH, blocked both phosphorylation and nuclear shuttling of mTOR in response to IR. These results indicate that alterations in PCPH expression may render tumor cells resistant to IR, and perhaps other DNA-damaging agents, by preventing mTOR activation and signaling.

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