p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis.
p38alpha is a stress-activated protein kinase that negatively regulates malignant transformation induced by oncogenic H-Ras, although the mechanisms involved are not fully understood. Here, we show that p38alpha is not a general inhibitor of oncogenic signaling, but that it specifically modulates transformation induced by oncogenes that produce reactive oxygen species (ROS). This inhibitory effect is due to the ROS-induced activation of p38alpha early in the process of transformation, which induces apoptosis and prevents the accumulation of ROS and their carcinogenic effects. Accordingly, highly tumorigenic cancer cell lines have developed a mechanism to uncouple p38alpha activation from ROS production. Our results indicate that oxidative stress sensing plays a key role in the inhibition of tumor initiation by p38alpha.
Dolado
Ignacio
I
CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Swat
Aneta
A
Ajenjo
Nuria
N
De Vita
Gabriella
G
Cuadrado
Ana
A
Nebreda
Angel R
AR
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D011905:Genes, ras / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D005982:Glutathione Transferase; D007527:Isoenzymes; D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D020830:rac1 GTP-Binding Protein; C412602:glutathione S-transferase Mu 2