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PKCdelta modulates p21WAF1/CIP1 ability to bind to Cdk2 during TNFalpha-induced apoptosis

You-Take Oh1, Kwang Hoon Chun, Jeong In Oh

  • 1College of Pharmacy, Division of Pharmaceutical Biosciences, Seoul National University, Seoul 151-742, Republic of Korea.

Biochemical and Biophysical Research Communications
|December 14, 2005
PubMed

Insights

Tumor necrosis factor alpha (TNFα) triggers apoptosis by activating protein kinase C delta (PKCδ). This enzyme phosphorylates p21(WAF1/CIP1), enhancing cyclin-dependent kinase 2 (Cdk2) activity during cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 2 (Cdk2) activity is implicated in chromatin condensation and other apoptotic cell death features.
  • Understanding the regulation of Cdk2 during apoptosis is crucial for deciphering cell fate mechanisms.

Purpose of the Study:

  • To investigate the role of protein kinase C delta (PKCδ) in regulating Cdk2 activity during TNFα-induced apoptosis.
  • To elucidate the molecular mechanism by which PKCδ influences p21(WAF1/CIP1) and its interaction with Cdk2.

Main Methods:

  • Utilized TNFα to induce apoptosis in relevant cellular models.
  • Assessed the activation of PKCδ and caspase-3.
  • Investigated the phosphorylation of p21(WAF1/CIP1) at Ser146.
  • Examined the interaction between p21(WAF1/CIP1) and Cdk2.

Main Results:

  • PKCδ activation was observed to be caspase-3-dependent during TNFα-induced apoptosis.
  • PKCδ phosphorylates p21(WAF1/CIP1) at Ser146, a site critical for Cdk2 binding.
  • Phosphorylation of p21(WAF1/CIP1) modulates its association with Cdk2.
  • This phosphorylation event correlates temporally with Cdk2 activation during apoptosis.

Conclusions:

  • PKCδ-mediated phosphorylation of p21(WAF1/CIP1) at Ser146 attenuates its binding to Cdk2.
  • This mechanism leads to the upregulation of Cdk2 activity during TNFα-induced apoptosis.
  • The findings reveal a novel regulatory pathway controlling Cdk2 activity in apoptotic processes.

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