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Extinction of rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway

P Lassus1, P Roux, O Zugasti

  • 1Institut de Génétique Moléculaire, CNRS UMR5535, IFR 24, 1919 Route de Mende, F-34293 Montpellier cedex 5, France.

Oncogene
|June 1, 2000
PubMed

Insights

Fibroblasts undergo apoptosis when detached, but Rac1 and Cdc42Hs GTPases can prevent this. These GTPases also trigger apoptosis in adherent cells, a process dependent on p53 and ERK signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis is a crucial physiological process for eliminating cells lacking extracellular signals.
  • The Rho family GTPases and the p53 tumor suppressor are key regulators of apoptosis.
  • Cell detachment from the extracellular matrix typically induces apoptosis.

Purpose of the Study:

  • To investigate the role of Rac1 and Cdc42Hs GTPases in regulating apoptosis upon cell detachment.
  • To elucidate the interplay between Rho GTPases, p53, and MAPK pathways in apoptosis signaling.

Main Methods:

  • Fibroblast cultures were subjected to detachment from the extracellular matrix.
  • Modulation of Rac1 and Cdc42Hs GTPase activity using genetic or pharmacological approaches.
  • Assessment of apoptosis using p53-deficient cells and specific MAPK pathway inhibitors (p38 and ERK).

Main Results:

  • Constitutive activation of Rac1 and Cdc42Hs GTPases rescued fibroblasts from apoptosis induced by detachment.
  • Inhibition of Rac1 and Cdc42Hs triggered apoptosis in adherent cells.
  • Apoptosis was abrogated in p53-deficient cells and Rac1/Cdc42Hs inhibition did not induce apoptosis.
  • Rac1 and Cdc42Hs depletion activated endogenous p53.
  • p38 MAPK signaling promoted survival, while ERK signaling was essential for apoptosis induction.

Conclusions:

  • Rac1 and Cdc42Hs GTPases play a critical role in controlling apoptosis, particularly in response to matrix detachment.
  • These GTPases regulate apoptosis through pathways involving both p53 and MAPK signaling (ERK).
  • The findings reveal a novel mechanism where Rac1 and Cdc42Hs integrate signals from p53 and MAPK pathways to dictate cell fate.

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