Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia-mutated Kinase Activity*

@article{Zhou2000CaffeineAT,
  title={Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia-mutated Kinase Activity*},
  author={Bin-Bing S. Zhou and Priya Chaturvedi and Kevin J. Spring and Shaun P. Scott and Roy A. Johanson and Rubin Mishra and Michael Mattern and James D. Winkler and Kum Kum Khanna},
  journal={The Journal of Biological Chemistry},
  year={2000},
  volume={275},
  pages={10342 - 10348}
}
Recent evidence indicates that arrest of mammalian cells at the G2/M checkpoint involves inactivation and translocation of Cdc25C, which is mediated by phosphorylation of Cdc25C on serine 216. Data obtained with a phospho-specific antibody against serine 216 suggest that activation of the DNA damage checkpoint is accompanied by an increase in serine 216 phosphorylated Cdc25C in the nucleus after exposure of cells to γ-radiation. Prior treatment of cells with 2 mm caffeine inhibits such a change… 

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References

SHOWING 1-10 OF 33 REFERENCES
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
TLDR
Results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2-cyclin B complex and mitotic entry.
Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
TLDR
Results indicate that serine-216 phosphorylation and 14-3-3 binding negatively regulate Cdc25C and identify CDC25C as a potential target of checkpoint control in human cells.
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
TLDR
Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosac charomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints, was identified and phosphorylated and activated in response to replication blocks and DNA damage.
Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
The p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53
ATM associates with and phosphorylates p53: mapping the region of interaction
TLDR
It is demonstrated that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.
Maintenance of G2 arrest in the Xenopus oocyte: a role for 14‐3‐3‐mediated inhibition of Cdc25 nuclear import
TLDR
Cdc25 in the G2‐arrested oocyte is bound to 14‐3‐3 proteins and that progesterone treatment abrogates this binding, demonstrating that Cdc25, apparently statically localized in the cytoplasm, is actually capable of shuttling in and out of the oocyte nucleus.
...
...