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Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription

Hilal S Khalil1, Hemanth Tummala, Tedd R Hupp

  • 1School of Contemporary Sciences, University of Abertay, Kydd Building, 40 Bell street, Dundee DD1 1HG, UK.

Experimental Biology and Medicine (Maywood, N.J.)
|June 26, 2012
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) kinase regulates DNA damage response. Inhibiting ATM kinase triggers its own induction and upregulates key proteins, offering new cancer therapy strategies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ataxia-telangiectasia mutated (ATM) kinase is crucial for DNA double-strand break (DSB) repair and the DNA damage response.
  • ATM activation by the MRN complex initiates signaling cascades, and ATM-deficient cells exhibit hypersensitivity to genotoxic stress.

Purpose of the Study:

  • To investigate ATM activation kinetics and downstream substrate phosphorylation during genotoxic agent treatment.
  • To elucidate a novel cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition.

Main Methods:

  • Time-dependent treatment with genotoxic agents.
  • Analysis of ATM activation, downstream substrate phosphorylation, and localization.
  • Investigation of ATM gene regulation via transcriptional mechanisms after ATM kinase inhibition with KU5593.

Main Results:

  • ATM kinase inhibition leads to a cell-cycle-independent induction of ATM protein, characterized by oscillation and transcriptional regulation.
  • This autoregulatory induction of ATM is accompanied by transient upregulation of p53, pATR, and E2F1.
  • ATM activation dynamics and downstream effects were characterized during genotoxic stress.

Conclusions:

  • A novel autoregulatory mechanism of ATM gene expression exists, governed transcriptionally and independent of the cell cycle.
  • Understanding this ATM regulation provides insights for developing targeted cancer therapies that modulate ATM activity.

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