Abstract
Adenovirus type 5 E1A protein (E1A) associates with anti-tumor activities by reversing the transformed phenotype, inhibiting metastasis, and inducing apoptosis. We have previously identified that E1A suppresses the expression of Axl, a transforming tyrosine kinase and that Axl-Gas6 receptor-ligand interaction prevents E1A transfectants from apoptosis induced by serum deprivation. To determine how the Axl-Gas6 interaction prevents E1A-mediated apoptosis, we analysed the expression of anti-apoptotic molecules and found that the activated form of Akt was suppressed in the E1A transfectant ip 1-E1A and that Gas6 was able to activate Akt in ip 1-E1A cells reexpressing Axl (ip 1-E1A-Axl). To determine whether activated Akt is required to prevent E1A-mediated apoptosis, ip 1-E1A-Axl cells were treated with the phosphatidylinositol-3′-OH kinase inhibitor wortmannin or transfected with a dominant negative Akt mutant. In both cases, Gas6 no longer protected the cells from serum deprivation-induced apoptosis. Thus, we conclude that activated Akt is required for Axl-Gas6 signaling to prevent E1A-mediated apoptosis induced by serum deprivation. Downstream molecules of Akt, including NF-κB, Fas ligand, and BAD were examined, among which phosphorylation of BAD by Axl-Gas6 signaling is associated with the anti-apoptotic activity of Akt in our study.
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Abbreviations
- dnAkt:
-
dominant negative Akt
- FACS:
-
fluorescence activated cell sorting
- GFP:
-
green fluorescent protein
- MAP kinase:
-
mitogen activated protein kinase
- PI(3):
-
phosphatidylinositol 3′-phosphate
- Wtmn:
-
Wortmannin
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Acknowledgements
This work was supported by NIH grants R01-CA 58880, R01-CA 77858, and SPORE in ovarian cancer 1 P50 CA 83639 (to M-C Hung).
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Lee, WP., Wen, Y., Varnum, B. et al. Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis. Oncogene 21, 329–336 (2002). https://doi.org/10.1038/sj.onc.1205066
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DOI: https://doi.org/10.1038/sj.onc.1205066
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