Abstract
The PTEN tumour suppressor1 and pro-apoptotic2 gene is frequently mutated in human cancers. We show that PTEN transcription is upregulated by Egr-1 after irradiation in wild-type, but not egr-1−/−, mice in vivo. We found that Egr-1 specifically binds to the PTEN 5′ untranslated region, which contains a functional GCGGCGGCG Egr-1-binding site. Inducing Egr-1 by exposing cells to ultraviolet light upregulates expression of PTEN messenger RNA and protein, and leads to apoptosis. egr-1−/− cells, which cannot upregulate PTEN expression after irradiation, are resistant to ultraviolet-light-induced apoptosis. Therefore, Egr-1 can directly regulate PTEN, triggering the initial step in this apoptotic pathway. Loss of Egr-1 expression, which often occurs in human cancers, could deregulate the PTEN gene and contribute to the radiation resistance of some cancer cells.
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Acknowledgements
We are indebted to A. Krones for her skilled assistance in providing mutant and wild-type mouse tissues. We thank E. Ruoslahti and J. Reed for comments on the manuscript. We are indebted to J. Milbrandt, Washington University Medical School, St Louis, for the gift of Egr-1 knockout animals. This work was supported by grants from the National Institutes of Health (E.D.A., D.M. and T.M.); from the Department of Defense (E.D.A. and I. de B.) and from the Tobacco Related Diseases Research Program of the University of California (I. de B.).
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Virolle, T., Adamson, E., Baron, V. et al. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol 3, 1124–1128 (2001). https://doi.org/10.1038/ncb1201-1124
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DOI: https://doi.org/10.1038/ncb1201-1124
