Ataxia telangiectasia mutated deficiency affects astrocyte growth but not radiosensitivity

Cancer Res. 1999 Oct 15;59(20):5294-8.

Abstract

The cancer-prone neurodegenerative disorder, ataxia telangiectasia (A-T), results from mutations of ATM (ataxia telangiectasia mutated). Individuals with A-T are also hypersensitive to ionizing radiation (IR). Cultured cells from A-T individuals or Atm-/- mice have cell cycle and growth defects and are generally considered radiosensitive. However, it has been shown recently that cell populations in the Atm-/- central nervous system are radioresistant. To define specific IR sensitivities of neural populations, we analyzed Atm-/- astrocytes. Here we show that Atm-/- astrocytes exhibit premature senescence, express constitutively high levels of p21, and have impaired p53 stabilization. However, in contrast to radiosensitive Atm-/- fibroblasts and radioresistant Atm-/- neurons, survival of Atm-/- astrocytes after IR was similar to wild-type astrocytes. Additionally, p53-null astrocytes, but not fibroblasts, were moderately more radioresistant than their wild-type counterparts, suggesting that the deficit in p53 stabilization observed in Atm-null cells is not a measure of radiation susceptibility. Thus, in astrocytes, the function of Atm in cellular growth and radiosensitivity is distinct. These data may have implications for ATM disruption strategies as a radiosensitizing treatment for brain tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Astrocytes / physiology
  • Astrocytes / radiation effects*
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Division
  • Cells, Cultured
  • DNA-Binding Proteins
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation
  • Proliferating Cell Nuclear Antigen / analysis
  • Protein Serine-Threonine Kinases*
  • Proteins / genetics
  • Proteins / physiology*
  • Radiation Tolerance*
  • Tumor Suppressor Protein p53 / physiology
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proliferating Cell Nuclear Antigen
  • Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases