C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death.
We present here evidences supporting a negative regulation of p38alpha MAPK activity by C3G in MEFs triggered by stress, which can mediate cell death or survival depending on the stimuli. Upon serum deprivation, C3G induces survival through inhibition of p38alpha activation, which mediates apoptosis. In contrast, in response to H2O2, C3G behaves as a pro-apoptotic molecule, as its knock-down or knock-out enhances survival through up-regulation of p38alpha activation, which plays an anti-apoptotic role under these conditions. Moreover, the C3G target, Rap-1, plays an opposite role, also through regulation of p38alpha MAPK activity. Our data also suggest that changes in the protein levels of some members of the Bcl-2 family could account for the regulation of cell death by C3G and/or Rap-1 through p38alpha MAPK. Bim/Bcl-xL ratio appears to be important in the regulation of cell survival, both upon serum deprivation and in response to H2O2. In addition, the increase in BNIP-3 levels induced by C3G knock-down in wt cells treated with H2O2 might play a role preventing cell death. Therefore, we can conclude that C3G is a negative regulator of p38alpha MAPK in MEFs, while Rap-1 is a positive regulator, but both, through the regulation of p38alpha activity, can promote cell survival or cell death depending on the stimuli.
Gutiérrez-Uzquiza
Alvaro
A
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain.
Arechederra
María
M
Molina
Isabel
I
Baños
Rocío
R
Maia
Vera
V
Benito
Manuel
M
Guerrero
Carmen
C
Porras
Almudena
A
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D015536:Down-Regulation; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D020735:Guanine Nucleotide-Releasing Factor 2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein; D006861:Hydrogen Peroxide; D048308:Mitogen-Activated Protein Kinase 14; D020827:rap1 GTP-Binding Proteins