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Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells

Jung-Sik Kim1, Xuehua Xu, Huifang Li

  • 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road, N.W., Washington, DC 20057, USA.

Molecular and Cellular Biology
|May 4, 2011
PubMed

Insights

DNA damage triggers cell cycle and cell size arrests. The tumor suppressor PTEN regulates this size checkpoint independently of Akt, interacting with an actin-remodeling complex to control cell size.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • DNA damage induces cell cycle arrests (G1, G2) and a cell size arrest.
  • The PTEN tumor suppressor gene is crucial for regulating cell size.
  • Previous work showed PTEN inactivation uncouples cell size from cell cycle arrest.

Purpose of the Study:

  • Investigate the regulation of the DNA damage-inducible cell size checkpoint.
  • Determine the role of PTEN and Akt in cell size control.
  • Identify PTEN regulators and effectors involved in the size checkpoint.

Main Methods:

  • Utilized DNA-damaging agents (chemotherapeutics, ionizing radiation).
  • Performed mutational analysis of PTEN and pharmacological inhibition of Akt.
  • Employed endogenous epitope tagging (EET) to identify PTEN interacting partners.
  • Assessed the impact of actin remodeling inhibition on cell size control.

Main Results:

  • The cell size checkpoint is inducible by DNA damage and regulated by PTEN, not PIK3CA.
  • Akt phosphorylation is not required for PTEN-mediated cell size checkpoint control.
  • Endogenous PTEN interacts with an actin-remodeling complex (actin, gelsolin, EPLIN) at the cell membrane.
  • Inhibiting actin remodeling phenocopies the lack of size checkpoint in PTEN-deficient cells.

Conclusions:

  • A DNA damage-inducible cell size checkpoint exists and is regulated by the tumor suppressor PTEN.
  • PTEN controls cell size through a novel, Akt-independent mechanism involving actin remodeling.
  • This study identifies a new pathway linking DNA damage, PTEN, and cell size regulation.

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