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Apoptotic and mitogenic stimuli inactivate Rb by differential utilization of p38 and cyclin-dependent kinases

Niharika Nath1, Sheng Wang, Vicki Betts

  • 1Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Oncogene
|September 5, 2003
PubMed

Insights

The retinoblastoma (Rb) protein is inactivated differently during cell cycle progression and apoptosis. Apoptotic signals inactivate Rb via p38 kinase, distinct from cell cycle pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • The retinoblastoma (Rb) protein is a critical tumor suppressor regulating cell cycle progression.
  • Rb inactivation by cyclin-dependent kinases (cdks) and their associated cyclins (D and E) is essential for the G1/S cell cycle transition.

Purpose of the Study:

  • To investigate the mechanism of Rb inactivation during apoptotic stimulation via Fas.
  • To compare Rb inactivation pathways during mitogenic progression versus apoptotic signaling.

Main Methods:

  • Western blotting to assess protein phosphorylation and interactions.
  • Analysis of Rb phosphorylation site mutants.
  • Functional assays to measure transcriptional activity.

Main Results:

  • Fas-induced apoptosis inactivates Rb through p38 kinase, independently of cyclins and cdks.
  • p38 kinase-mediated Rb inactivation increases phosphorylation, dissociates E2F, and enhances transcriptional activity.
  • p38 kinase preferentially targets Rb, with minimal effects on p107 and no effect on p130.
  • Rb mutants resistant to cdk inactivation are still targeted by Fas and p38 kinase.

Conclusions:

  • Rb inactivation occurs via distinct kinase cascades in response to mitogenic and apoptotic signals.
  • p38 kinase represents a novel pathway for Rb inactivation during apoptosis, separate from cell cycle control mechanisms.

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