Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress

Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / enzymology*
  • Cell Nucleus / metabolism
  • Cisplatin / pharmacology
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA Repair*
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Morpholines / pharmacology
  • Neoplasm Transplantation
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Sumoylation
  • Transplantation, Heterologous
  • Tumor Suppressor Proteins / metabolism

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Morpholines
  • NVP-BKM120
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Suppressor Proteins
  • Doxorubicin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse
  • Cisplatin