title: Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.
abstract: 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.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Bassi
authors.forename: J
authors.initials: J
authors.lastname: Ho
authors.forename: T
authors.initials: T
authors.lastname: Srikumar
authors.forename: R J O
authors.initials: RJ
authors.lastname: Dowling
authors.forename: C
authors.initials: C
authors.lastname: Gorrini
authors.forename: S J
authors.initials: SJ
authors.lastname: Miller
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: B G
authors.initials: BG
authors.lastname: Neel
authors.forename: B
authors.initials: B
authors.lastname: Raught
authors.forename: V
authors.initials: V
authors.lastname: Stambolic
mesh_terms: D021581:Active Transport, Cell Nucleus; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D058207:Sumoylation; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D002945:Cisplatin