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Molecular and Cellular Biology, November 2002, p. 7831-7841, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7831-7841.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activation of Akt/Protein Kinase B Overcomes a G₂/M Cell Cycle Checkpoint Induced by DNA Damage

Eugene S. Kandel,^1, Jennifer Skeen,¹ Nathan Majewski,¹ Antonio Di Cristofano,^2, Pier Paolo Pandolfi,² Claudine S. Feliciano,¹ Andrei Gartel,¹ and Nissim Hay^1*

Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607,¹ Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York²

Received 30 April 2002/ Returned for modification 17 June 2002/ Accepted 20 August 2002

Activation of Akt, or protein kinase B, is frequently observed in human cancers. Here we report that Akt activation via overexpression of a constitutively active form or via the loss of PTEN can overcome a G₂/M cell cycle checkpoint that is induced by DNA damage. Activated Akt also alleviates the reduction in CDC2 activity and mitotic index upon exposure to DNA damage. In addition, we found that PTEN null embryonic stem (ES) cells transit faster from the G₂/M to the G₁ phase of the cell cycle when compared to wild-type ES cells and that inhibition of phosphoinositol-3-kinase (PI3K) in HEK293 cells elicits G₂ arrest that is alleviated by activated Akt. Furthermore, the transition from the G₂/M to the G₁ phase of the cell cycle in Akt1 null mouse embryo fibroblasts (MEFs) is attenuated when compared to that of wild-type MEFs. These results indicate that the PI3K/PTEN/Akt pathway plays a role in the regulation of G₂/M transition. Thus, cells expressing activated Akt continue to divide, without being eliminated by apoptosis, in the presence of continuous exposure to mutagen and accumulate mutations, as measured by inactivation of an exogenously expressed herpes simplex virus thymidine kinase (HSV-tk) gene. This phenotype is independent of p53 status and cannot be reproduced by overexpression of Bcl-2 or Myc and Bcl-2 but seems to counteract a cell cycle checkpoint mediated by DNA mismatch repair (MMR). Accordingly, restoration of the G₂/M cell cycle checkpoint and apoptosis in MMR-deficient cells, through reintroduction of the missing component of MMR, is alleviated by activated Akt. We suggest that this new activity of Akt in conjunction with its antiapoptotic activity may contribute to genetic instability and could explain its frequent activation in human cancers.

Present address: The Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195.

Present address: Fox Chase Cancer Center, Philadelphia, PA 19111.

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