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Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage

Eugene S Kandel1, Jennifer Skeen, Nathan Majewski

  • 1Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

Molecular and Cellular Biology
|October 23, 2002
PubMed

Insights

Activated Akt protein kinase B bypasses DNA damage checkpoints, promoting cell division and mutation accumulation. This PI3K/PTEN/Akt pathway activity contributes to genetic instability in cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Biology

Background:

  • Activation of Akt (protein kinase B) is common in human cancers.
  • The PI3K/PTEN/Akt pathway is crucial for cell growth and survival.
  • DNA damage can induce cell cycle checkpoints to prevent mutations.

Purpose of the Study:

  • To investigate the role of Akt activation in overcoming DNA damage-induced cell cycle checkpoints.
  • To determine how the PI3K/PTEN/Akt pathway influences cell cycle progression after DNA damage.
  • To explore the implications of Akt activity on genetic instability and cancer development.

Main Methods:

  • Overexpression of constitutively active Akt or loss of PTEN in cancer cells and embryonic stem cells.
  • Inhibition of phosphoinositol-3-kinase (PI3K) and assessment of cell cycle arrest.
  • Analysis of G(2)/M to G(1) phase transition in Akt1 null and wild-type mouse embryo fibroblasts (MEFs).
  • Measurement of mutation accumulation using the herpes simplex virus thymidine kinase (HSV-tk) gene assay.
  • Investigation of the interaction between Akt and DNA mismatch repair (MMR) pathways.

Main Results:

  • Activated Akt overcomes the G(2)/M cell cycle checkpoint induced by DNA damage.
  • Akt activation alleviates reduced CDC2 activity and mitotic index upon DNA damage.
  • PTEN-null cells and cells with activated Akt show faster G(2)/M to G(1) transition.
  • Akt inhibition causes G(2) arrest, which is rescued by activated Akt.
  • Akt1-null MEFs exhibit attenuated G(2)/M to G(1) transition compared to wild-type.
  • Cells with activated Akt accumulate mutations and resist apoptosis despite DNA damage.
  • Activated Akt counteracts checkpoints mediated by DNA mismatch repair (MMR).

Conclusions:

  • The PI3K/PTEN/Akt pathway is a key regulator of G(2)/M cell cycle transition.
  • Activated Akt promotes cell division and mutation accumulation in the presence of DNA damage.
  • Akt's anti-apoptotic and cell cycle-promoting activities contribute to genetic instability in cancer.
  • This pathway's role in genetic instability may explain its frequent activation in human cancers.

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