PTENGene Targeting Reveals a Radiation-Induced Size Checkpoint in Human Cancer Cells
- 1 October 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 64 (19) , 6906-6914
- https://doi.org/10.1158/0008-5472.can-04-1767
Abstract
Following DNA damage, human cells arrest primarily in the G1 and G2 phases of the cell cycle. Here, we show that after irradiation, human cancer cells with targeted deletion of PTEN or naturally occurring PTEN mutations can exert G1 and G2 arrests but are unable to arrest in size. Pharmacological inhibition of phosphoinositol-3-kinase or mTOR in PTEN−/− cells restored the size arrest, whereas siRNA-mediated depletion of TSC2 in PTEN+/+ cells attenuated the size arrest. Radiation treatment potentiated Akt activation in PTEN−/− but not PTEN+/+ cells. Finally, abrogation of the size arrest via PTEN deletion conferred radiosensitivity both in vitro and in vivo. These results identify a new tumor suppressor gene-regulated, DNA damage-inducible arrest that occurs simultaneously with the G1 and G2 arrests but is genetically separable from them. We suggest that aberrant regulation of cell size during cell cycle arrest may be important in human cancer pathogenesis.Keywords
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