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Inhibition of the ATR/Chk1 pathway induces a p38-dependent S-phase delay in mouse embryonic stem cells

Ludmila Jirmanova1, Dmitry V Bulavin, Albert J Fornace

  • 1Laboratory of Immune Cell Biology, National Cancer Institute, Bethesda, Maryland, USA.

Cell Cycle (Georgetown, Tex.)
|September 3, 2005
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases are vital for genomic stability. ATR kinase is essential for mouse embryonic stem cell cycle progression, and its deregulation triggers p38alpha-dependent checkpoints and apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases are crucial for DNA damage response and genomic stability.
  • These kinases are part of the PI-3 kinase-related protein family.

Purpose of the Study:

  • To investigate the roles of ATR and ATM kinases in the embryonic cell cycle using wild-type and p38alpha-deficient mouse embryonic stem (ES) cells.
  • To elucidate the involvement of ATR and ATM in checkpoint activation and apoptosis.

Main Methods:

  • Inhibition of ATR and ATM kinases using caffeine.
  • Inhibition of Chk1 using UCN-01.
  • Utilized wild-type (WT) and p38alpha-deficient mouse embryonic stem (ES) cells.
  • Wortmannin was used to selectively inhibit ATM kinase.

Main Results:

  • Inhibition of ATR/ATM kinases activated a p38-dependent intra-S-phase checkpoint and apoptosis in ES cells.
  • Wortmannin, inhibiting only ATM, did not affect cell cycle progression.
  • Caffeine treatment led to p38 kinase activation, p21/Waf1 accumulation, and decreased Cdk2 activity.
  • p38alpha-/- ES cells showed reduced apoptosis and failed to activate the S-phase checkpoint upon caffeine treatment.

Conclusions:

  • ATR kinase activity is essential for the normal cell cycle progression of proliferating mouse ES cells, even without exogenous DNA damage.
  • ATR deregulation initiates p38alpha-dependent cell-cycle checkpoint and apoptotic responses.

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