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Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells

Oncogene volume 21, pages 4032–4041 (2002)Cite this article

Abstract

In this study we have investigated the effects of low dose ionizing radiation (2 Gy) on p70 S6 kinase and Akt signaling with respect to Erb-B receptors in both the A431 squamous and the MDA-MB-231 mammary carcinoma cell lines. Ionizing radiation caused a 2–3-fold increase in p70 S6 kinase activity that was blocked pharmacologically using an EGFR inhibitor (AG1478) alone, or in combination with an Erb-B2 inhibitor (AG825). These results suggested that both EGFR and Erb-B2 receptors could initiate radiation-induced activation of p70 S6K. EGFR dependent Erb-B3 signaling also contributed to p70 S6 kinase activity through recruitment and activation of PI3K, which has been shown to regulate p70 S6 kinase activity. Furthermore, inhibition of the EGFR blocked IR stimulated increases in protein translation, a biologic consequence of p70 S6 kinase activation. We also report that ionizing radiation stimulated Akt activity that was partially independent of PI3K activity, but dependent on Erb-B2 function. Erb-B2 inhibition also correlated with enhanced apoptosis following IR exposure, suggesting an important role for Erb-B2 in cell survival. Together this work demonstrates that the Erb-B receptor tyrosine kinase network stimulates cytoprotective p70 S6 kinase and Akt activity in response to clinically relevant doses of ionizing radiation.

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Acknowledgements

This work is dedicated to Joseph V Contessa, with gratitude for his support as a teacher, advisor, and friend. The research was supported by PHS Grants P01 CA72955, R01 CA65896, the US DOD DAMD17-99-1-9426, and by the Florence Hyman Meyers Head and Neck Cancer Research Fund.

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  1. The Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, 23298, Richmond, Virginia, VA, USA

    Joseph N Contessa, Jaime Hampton, Guido Lammering, Ross B Mikkelsen, Paul Dent, Kristoffer Valerie & Rupert K Schmidt-Ullrich

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  1. Joseph N Contessa
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  3. Guido Lammering
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Contessa, J., Hampton, J., Lammering, G. et al. Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. Oncogene 21, 4032–4041 (2002). https://doi.org/10.1038/sj.onc.1205500

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