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C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death

Alvaro Gutiérrez-Uzquiza1, María Arechederra, Isabel Molina

  • 1Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain.

Cellular Signalling
|November 21, 2009
PubMed

Insights

C3G negatively regulates p38alpha MAPK activity in mouse embryonic fibroblasts (MEFs), influencing cell death or survival based on stress type. Rap-1 has an opposite role, with both impacting cell fate via p38alpha MAPK signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signaling Pathways

Background:

  • p38alpha MAPK is a key regulator of cellular responses to stress.
  • C3G and Rap-1 are signaling molecules involved in cellular processes.
  • The interplay between C3G, Rap-1, and p38alpha MAPK in stress-induced cell fate decisions is not fully understood.

Purpose of the Study:

  • To investigate the role of C3G in regulating p38alpha MAPK activity under different stress conditions.
  • To elucidate the downstream mechanisms by which C3G influences cell survival or death.
  • To determine the role of Rap-1 in this signaling pathway.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) subjected to serum deprivation and hydrogen peroxide (H2O2) stress.
  • Assessed p38alpha MAPK activity, C3G and Rap-1 levels, and expression of Bcl-2 family proteins.
  • Employed gene knockdown and knockout strategies for C3G.

Main Results:

  • C3G acts as a negative regulator of p38alpha MAPK activity in MEFs.
  • Under serum deprivation, C3G promotes survival by inhibiting p38alpha MAPK.
  • In response to H2O2, C3G promotes apoptosis via p38alpha MAPK, while its absence enhances survival.
  • Rap-1 exhibits an opposing regulatory role through p38alpha MAPK.
  • Bcl-2 family members, including the Bim/Bcl-xL ratio and BNIP-3, are implicated in C3G-mediated cell fate determination.

Conclusions:

  • C3G is a negative regulator of p38alpha MAPK in MEFs, while Rap-1 is a positive regulator.
  • Both C3G and Rap-1 modulate cell survival or death by regulating p38alpha MAPK activity, with outcomes dependent on the specific stress stimulus.
  • The Bcl-2 family proteins play a crucial role in mediating these C3G and Rap-1 effects on cell fate.

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