Abstract
2-Aminopurine (2-AP) is an adenine analog shown to cause cells to bypass chemical- and radiation-induced cell cycle arrest through as-yet unidentified mechanisms. 2-AP has also been shown to act as a kinase inhibitor. Tumor suppressor p53 plays an important role in the control of cell cycle and apoptosis in response to genotoxic stress. We were interested in examining the effect of 2-AP on p53 phosphorylation and its possible consequences on checkpoint control in cells subjected to various forms of DNA damage. Here, we show that 2-AP suppresses p53 phosphorylation in response to gamma radiation, adriamycin, or ultraviolet treatment. This is partly explained by the ability of the kinase inhibitor to inhibit ATM or ATR activities in vitro and impair ATM- or ATR-dependent p53 phosphorylation in vivo. However, 2-AP is also capable of inhibiting p53 phosphorylation in cells deficient in ATM, DNA-PK, or ATR suggesting the existence of multiple pathways by which this kinase inhibitor modulates p53 activation. Biologically, the 2-AP-mediated inhibition of p53 stabilization enables wild-type p53-containing cells to bypass adriamycin-induced G2/M arrest. In the long term, however, 2-AP facilitates cells to resist DNA damage-induced cell death independently of p53.
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Acknowledgements
We are grateful to M Kastan for Flag-ATMwt expression vector; S Elledge for anti-mouse Chk2 antibodies; B Vogelstein for HCT116 cell lines; S Handeli for tetracycline-inducible ATR cell lines; R Lin for 293T cells; C Autexier for WI-38 cells; T Halazonetis, G Ferbeyre and members of our lab for helpful discussions. This work was supported by a research grant from the National Cancer Institute of Canada to AEK. AEK is a recipient of a Scientist Award from the Canadian Institutes for Health Research (CIHR).
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Huang, S., Qu, LK., Cuddihy, A. et al. Protein kinase inhibitor 2-aminopurine overrides multiple genotoxic stress-induced cellular pathways to promote cell survival. Oncogene 22, 3721–3733 (2003). https://doi.org/10.1038/sj.onc.1206490
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DOI: https://doi.org/10.1038/sj.onc.1206490
