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A New Role of Protein Phosphatase 2A in Adenoviral E1A Protein-Mediated Sensitization to Anticancer Drug-Induced Apoptosis in Human Breast Cancer Cells

Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

The adenoviral type 5 E1A protein has been shown to induce sensitization to different categories of anticancer drug-induced apoptosis, partly by down-regulation of the activity of a critical oncogenic kinase Akt in both normal fibroblasts and epithelial breast cancer cells. Currently, the adenoviral E1A gene is being tested as an antitumor gene in multiple clinical trials. However, molecular mechanisms underlying E1A-mediated chemosensitization and down-regulation of Akt activity are still not completely defined. Here, we show that E1A by up-regulation of the catalytic subunit of protein phosphatase 2A [PP2A (PP2A/C)] enhanced the activity of PP2A, which results in repression of Akt activation in E1A-expressing cells. In addition, activation of PP2A/C is required for E1A-mediated sensitization to drug-induced apoptosis, because blocking PP2A/C expression using a specific small interfering RNA against PP2A/C reduced drug sensitivity in E1A-expressing cells. Deletion mutation of the conserved domain of E1A, which is required for E1A-mediated sensitization to drug-induced apoptosis, also abolished the ability of E1A to up-regulate PP2A/C. Thus, the up-regulation of PP2A may represent a novel mechanism for E1A-mediated sensitization to anticancer drug-induced apoptosis.

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