Journal
SCIENCE
Volume 341, Issue 6144, Pages 395-399Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1236188
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Funding
- Canadian Cancer Society [2011-700891]
- NIH [R37 CA49152]
- Ontario Ministry of Health and Long Term Care
- Princess Margaret Hospital Foundation
- Excellence in Radiation Research for the 21st century (EIRR21st) fellowship
- Canadian Institutes of Health Research
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Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.
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