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The E6AP E3 ubiquitin ligase regulates the cellular response to oxidative stress

Oncogene volume 32, pages 3510–3519 (2013)Cite this article

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Abstract

The E6AP E3 ubiquitin ligase has been linked to the regulation of cell growth and to the cellular stress response. However, the specific stress conditions that are controlled by E6AP have not been defined. An important stress condition that controls cell growth is oxidative stress, where the levels of intracellular reactive oxygen species (ROS) regulate the appropriate cellular response. Here, we describe a novel role for E6AP in the control of oxidative stress response. Cells lacking E6AP expression have reduced capacity to accumulate ROS, and oxidative DNA damage, in response to 20% cell culture oxygen levels, treatment with hydrogen peroxide and expression of oncogenic RAS. This effect of E6AP is associated with the regulation of the anti-oxidant enzyme, Prx1, a previously identified target of E6AP, and can be corrected by downregulation of Prx1 or by reconstitution of E6AP expression. Consequently, cells with compromised E6AP have impaired senescent and apoptotic response to sub-lethal and lethal doses of oxidative stress, respectively. In a xenograft model, downregulation of E6AP renders transplanted tumours refractory to growth-suppressive effects of hydrogen peroxide. Our results provide the first demonstration that E6AP is an important regulator of ROS-mediated cellular senescence and cell death.

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Acknowledgements

We thank Scott Lowe, Martin Scheffner and Ikuo Shoji who generously provided plasmids. This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia to YH (NHMRC #509196, #509197, #1026990, #1026988), by a grant from the Cancer Council Victoria, and by the VESKI award. YH is NHMRC Senior Research Fellow.

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Authors and Affiliations

  1. Tumour Suppression Laboratory, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    K Wolyniec, S Haupt & Y Haupt

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    K Wolyniec, S Haupt & Y Haupt

  3. The Hebrew University Hadassah Medical School, Jerusalem, Israel

    Y Levav-Cohen

  4. Division of Medical Genetics, Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC, USA

    Y-H Jiang

  5. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia

    Y Haupt

  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

    Y Haupt

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Correspondence to Y Haupt.

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Wolyniec, K., Levav-Cohen, Y., Jiang, YH. et al. The E6AP E3 ubiquitin ligase regulates the cellular response to oxidative stress. Oncogene 32, 3510–3519 (2013). https://doi.org/10.1038/onc.2012.365

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