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Cdk2 activation acts upstream of the mitochondrion during glucocorticoid induced thymocyte apoptosis

Francesc Granés1, Maurici B Roig, Hugh J M Brady

  • 1Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica-Universitat Pompeu Fabra, Barcelona, Spain.

European Journal of Immunology
|September 16, 2004
PubMed

Insights

Cyclin-dependent kinase 2 (Cdk2) activation is an early step in thymocyte apoptosis, preceding caspase activation. This kinase is essential for mitochondrial dysfunction and downstream caspase activation in DNA damage and glucocorticoid-induced apoptosis.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Thymocytes undergo apoptosis during negative selection and in response to glucocorticoids or DNA-damaging agents.
  • While post-mitochondrial apoptotic events are known, the pathways linking initial stimuli to mitochondrial dysfunction remain unclear.
  • Activation of the kinase Cdk2 is specifically observed in these apoptotic pathways.

Purpose of the Study:

  • To elucidate the role of Cdk2 activation in the early stages of thymocyte apoptosis.
  • To determine the position of Cdk2 activation within the apoptotic signaling cascade.
  • To define the necessity of Cdk2 for mitochondrial disruption and subsequent caspase activation.

Main Methods:

  • Investigated the temporal relationship between Cdk2 activation, caspase activation, and phosphatidylserine exposure.
  • Assessed the requirement of Cdk2 activation for mitochondrial permeability transition, cytochrome c release, and downstream caspase activation.
  • Utilized in vitro models of thymocyte apoptosis induced by DNA-damaging drugs and glucocorticoids.

Main Results:

  • Cdk2 activation was identified as a very early event in thymocyte apoptosis, preceding apical caspase activation and phosphatidylserine exposure.
  • Cdk2 activation was found to be obligatory for the disruption of mitochondrial permeability and the release of cytochrome c.
  • Consequently, Cdk2 activation is essential for the activation of downstream caspases 9 and 3.

Conclusions:

  • An integrated, linear pathway for DNA damage and glucocorticoid-induced thymocyte apoptosis is proposed, with Cdk2 activation as a critical early regulator.
  • Cdk2 acts upstream of mitochondrial dysfunction and apical caspase activation in these apoptotic pathways.
  • These findings provide new insights into the molecular mechanisms governing thymocyte apoptosis.

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