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Journal of Oncology
Volume 2012 (2012), Article ID 951724, 15 pages
http://dx.doi.org/10.1155/2012/951724
Review Article

Akt: A Double-Edged Sword in Cell Proliferation and Genome Stability

1Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
2School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Cai Lun Lu 1200, Shanghai 201203, China
3The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
4College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK

Received 26 October 2011; Accepted 29 December 2011

Academic Editor: Richard T. Penson

Copyright © 2012 Naihan Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis. Growth-factor-activated Akt signalling promotes progression through normal, unperturbed cell cycles by acting on diverse downstream factors involved in controlling the G1/S and G2/M transitions. Remarkably, several recent studies have also implicated Akt in modulating DNA damage responses and genome stability. High Akt activity can suppress ATR/Chk1 signalling and homologous recombination repair (HRR) via direct phosphorylation of Chk1 or TopBP1 or, indirectly, by inhibiting recruitment of double-strand break (DSB) resection factors, such as RPA, Brca1, and Rad51, to sites of damage. Loss of checkpoint and/or HRR proficiency is therefore a potential cause of genomic instability in tumor cells with high Akt. Conversely, Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ). Akt therefore modifies both the response to and repair of genotoxic damage in complex ways that are likely to have important consequences for the therapy of tumors with deregulation of the PI3K-Akt-PTEN pathway.