Publication Date:
2013-07-28
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bassi, C -- Ho, J -- Srikumar, T -- Dowling, R J O -- Gorrini, C -- Miller, S J -- Mak, T W -- Neel, B G -- Raught, B -- Stambolic, V -- R37 CA49152/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888040" target="_blank"〉PubMed〈/a〉
Keywords:
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/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/*metabolism
;
Phosphatidylinositol 3-Kinase/antagonists & inhibitors
;
Phosphorylation
;
Protein-Serine-Threonine Kinases/metabolism
;
Sumoylation
;
Transplantation, Heterologous
;
Tumor Suppressor Proteins/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
