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Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes

Jeesun Kim1, Paul K Y Wong

  • 1Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville, TX 78957, USA.

The Journal of Biological Chemistry
|March 27, 2009
PubMed

Insights

Ataxia-telangiectasia (A-T) astrocytes exhibit impaired growth due to elevated reactive oxygen species (ROS). ATM protein kinase is crucial for stabilizing cellular redox status, preventing senescence-like defects in astrocytes.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Ataxia-telangiectasia (A-T) is characterized by progressive neurodegeneration.
  • Primary astrocytes from Atm(-/-) mice show reduced growth and survival in culture.
  • The underlying mechanisms for A-T astrocyte dysfunction are not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms behind the impaired growth of Atm(-/-) astrocytes.
  • To investigate the role of reactive oxygen species (ROS) in A-T astrocyte senescence.
  • To identify potential therapeutic targets for A-T neurodegeneration.

Main Methods:

  • Primary astrocyte cultures from Atm(-/-) and control mice.
  • Measurement of intracellular ROS levels.
  • Analysis of ERK1/2 phosphorylation, p16(Ink4a), and Bmi-1 expression.
  • Treatment with MAPK/ERK inhibitor (PD98059) and antioxidant (N-acetyl-l-cysteine).

Main Results:

  • Atm(-/-) astrocytes display elevated intracellular ROS and a senescence-like growth defect.
  • Increased ERK1/2 phosphorylation and p16(Ink4a) levels were observed in Atm(-/-) astrocytes.
  • ROS-induced p16(Ink4a) up-regulation correlated with ERK1/2-dependent Bmi-1 downregulation.
  • PD98059 and N-acetyl-l-cysteine treatment rescued the proliferation defect in Atm(-/-) astrocytes.

Conclusions:

  • ATM is essential for maintaining normal astrocyte growth by stabilizing intracellular redox status.
  • Impaired ROS control is the molecular basis for limited Atm(-/-) astrocyte growth.
  • A mechanism involving ERK1/2 activation and Bmi-1 regulation of p16(Ink4a) may mediate the defect.
  • These findings suggest potential therapeutic targets for A-T neurodegeneration.

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