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PTEN Gene Targeting Reveals a Radiation-Induced Size Checkpoint in Human Cancer Cells

¹ Department of Oncology and ² Tumor Biology Training Program, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia

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.

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