Protein kinase inhibitor 2-aminopurine overrides multiple genotoxic stress-induced cellular pathways to promote cell survival.
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 G(2)/M arrest. In the long term, however, 2-AP facilitates cells to resist DNA damage-induced cell death independently of p53.
Huang
Shirley
S
Department of Microbiology and Immunology, McGill University, Montreal, Canada H3A 2T5.
Qu
Li-Ke
LK
Cuddihy
Andrew R
AR
Ragheb
Rafik
R
Taya
Yoichi
Y
Koromilas
Antonis E
AE
D015075:2-Aminopurine / Q000494:pharmacology*; D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015075:2-Aminopurine; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases