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Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by α-lipoic acid

Oncogene volume 20, pages 289–294 (2001)Cite this article

Abstract

Cells from patients with the genetic disorder ataxia-telangiectasia (A-T) are hypersensitive to ionizing radiation and radiomimetic agents, both of which generate reactive oxygen species capable of causing oxidative damage to DNA and other macromolecules. We describe in A-T cells constitutive activation of pathways that normally respond to genotoxic stress. Basal levels of p53 and p21WAF1/CIP1, phosphorylation on serine 15 of p53, and the Tyr15-phosphorylated form of cdc2 are chronically elevated in these cells. Treatment of A-T cells with the antioxidant α-lipoic acid significantly reduced the levels of these proteins, pointing to the involvement of reactive oxygen species in their chronic activation. These findings suggest that the absence of functional ATM results in a mild but continuous state of oxidative stress, which could account for several features of the pleiotropic phenotype of A-T.

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Acknowledgements

We thank Luciana Chessa for A-T lymphoblastoid cell lines. This study was supported by the National Health and Medical Research Council of Australia, the A-T Medical Research Foundation, the AT Children's Project, the Queensland Cancer Fund, NIH grants NS31763 (to Y Shiloh) and NS34746 (to TK Pandita), the Thomas Appeal (A-T Medical Research Trust) and the A-T Appeal.

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  1. Magtouf Gatei and Dganit Shkedy: M Gatei and D Shkedy contributed equally to this work

Authors and Affiliations

  1. Queensland Cancer Fund Research Laboratories, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane, Qld, 4029, Australia

    Magtouf Gatei, Kum Kum Khanna & Martin F Lavin

  2. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel

    Dganit Shkedy, Tamar Uziel, Yosef Shiloh & Galit Rotman

  3. Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, 10032, NY, USA

    Tej K Pandita

  4. Department of Surgery, The University of Queensland, PO Royal Brisbane Hospital, Herston, Brisbane, Qld. 4029, Australia

    Martin F Lavin

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Gatei, M., Shkedy, D., Khanna, K. et al. Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by α-lipoic acid. Oncogene 20, 289–294 (2001). https://doi.org/10.1038/sj.onc.1204111

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