Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM

@article{Hickson2004IdentificationAC,
  title={Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM},
  author={Ian D. Hickson and Yan Zhao and Caroline J. Richardson and Sharon J Green and Niall M. B. Martin and Alisdair I Orr and Philip Michael Reaper and Stephen P. Jackson and Nicola J. Curtin and Graeme C M Smith},
  journal={Cancer Research},
  year={2004},
  volume={64},
  pages={9152 - 9159}
}
The serine/threonine protein kinase ATM signals to cell cycle and DNA repair components by phosphorylating downstream targets such as p53, CHK2, NBS1, and BRCA1. Mutation of ATM occurs in the human autosomal recessive disorder ataxia-telangiectasia, which is characterized by hypersensitivity to ionizing radiation and a failure of cells to arrest the cell cycle after the induction of DNA double-strand breaks. It has thus been proposed that ATM inhibition would cause cellular radio- and… Expand
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References

SHOWING 1-10 OF 67 REFERENCES
Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products
TLDR
A biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes is demonstrated. Expand
Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin.
TLDR
Wortmannin is identified as an inhibitor of ATM activity and it is suggested that ATM and DNA-PK are relevant targets for the radiosensitizing effect of this drug in cancer cells. Expand
ATM: from gene to function.
TLDR
It is shown that ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic or V(D)J recombination, which involve the activation of cell cycle checkpoints, DNA repair and apoptosis. Expand
Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.
TLDR
In vivo, results suggest that in vivo, Chk2 is directly phosphorylated by ATM in response to IR and that Chk 2 is regulated by phosphorylation of the SCD. Expand
ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
TLDR
Observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases. Expand
Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites.
TLDR
Tumour-targeted functional inhibition of ATM may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers. Expand
Enhanced phosphorylation of p53 by ATM in response to DNA damage.
TLDR
Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM, and this activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug. Expand
ATM as a target for novel radiosensitizers.
TLDR
Interestingly, caffeine and other methyl xanthines preferentially radiosensitize cells that lack normal p53 function, which suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues. Expand
The genetic defect in ataxia-telangiectasia.
TLDR
The pleiotropic nature of the clinical and cellular phenotype suggests that the gene product involved is important in maintaining stability of the genome but also plays a more general role in signal transduction. Expand
Enhanced sensitivity to camptothecin in ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I.
TLDR
Cell cycle delay and cell killing by CPT in primary and transformed fibroblasts, and in lymphoblastoid lines derived from normal, X-ray sensitive ataxia-telangiectasia and xeroderma pigmentosum donors, and the contribution made by topoisomerase I-dependent damage to the cytotoxic action of CPT are measured. Expand
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