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E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

Abstract

Cellular senescence is important for the maintenance of tissue homeostasis, and has recently been shown to pose a natural barrier to tumorigenesis. The E3 ubiquitin ligase, E6AP, has been linked to a number of protein regulators of the cell cycle as well as the cellular stress response. We therefore explored the role of E6AP in the cellular response to stress. We found that mouse embryo fibroblasts (MEFs) lacking E6AP escape replicative senescence, as well as Ras-induced senescence associated with impaired markers. E6AP-deficient MEFs exhibit a range of transformed phenotypes: these include the ability to grow under stress conditions (such as low serum and DNA damage), enhanced proliferation, anchorage independent growth and enhanced growth of xenografts in mice. The transformed phenotype of E6AP-deficient MEFs is associated with lower basal and stress-induced accumulation of p53. Overall, our study implicates E6AP as an important regulator of the cellular response to stress, in particular through the regulation of replicative and oncogene-induced senescence.

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Acknowledgements

We express our thanks to Scott Lowe and Martin Scheffner for the generous gifts of expression plasmids, and to Mariam Mansour for critical comments on the manuscript. Work in the authors laboratory is supported by an NHMRC project grant (grant No. 509196), by a grant from the Cancer Council Victoria, by the VESKI award and by the EC FP6 funding of the European commission (contract 503576). This publication reflects only the authors' views. The European commission is not liable for any use that may be made of the information herein.

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Levav-Cohen, Y., Wolyniec, K., Alsheich-Bartok, O. et al. E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts. Oncogene 31, 2199–2209 (2012). https://doi.org/10.1038/onc.2011.402

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