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E1A Inhibition of Radiation-induced NF-B Activity through Suppression of IKK Activity and IB Degradation, Independent of Akt Activation¹

Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Activation of the transcription factor nuclear factor B (NF-B) has been implicated in the protection of cells from apoptosis. We have shown previously that the adenovirus type 5 E1A sensitizes cells to radiation-induced apoptosis by inhibiting NF-B activity. However, the exact mechanism of inhibition is not known. In this study, we compared the activity of inhibitor of nuclear factor-B (IB) kinase (IKK) and the degradation of IB in E1A transfectants and parental human cancer cells after ionizing radiation treatment. We found that radiation-induced IKK activity and IB degradation were inhibited in the E1A transfectants. Recently, Akt has been implicated in NF-B activation. To test whether Akt is regulated by E1A and is involved in radiation-induced NF-B activity, we examined the phosphorylation status of Akt in the E1A transfectants and parental cells and in irradiated cells. The results indicated that radiation induced Akt phosphorylation and that E1A inhibited basal but not radiation-induced Akt phosphorylation. We additionally examined radiation-induced NF-B activity in cells stably transfected with a dominant-negative, inactive Akt and in parental cancer cells treated with a phosphatidylinositol 3-kinase inhibitor, wortmannin. We found that dominant-negative Akt and wortmannin did not block radiation-induced NF-B activity. Thus, our results suggest that inhibition of IKK activity and IB degradation is the predominant mechanism for E1A-mediated inhibition of radiation-induced NF-B activity and that radiation-induced Akt activation cannot be inhibited by E1A and is likely independent of radiation-induced NF-B activity.

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