Phosphorylation and transcriptional activation of c-Fos by members of the p38 MAPK family.

TAMARA TANOS; MARIA J. MARINISSEN; J.. SILVIO GUTKIND; & OMAR A. COSO

Madrid ESPANA

Congreso; CNIO CANCER CONFERENCE: MAPK and CANCER; 2005

CNIO

Phosphorylation and transcriptional activation of c-Fos by members of the p38 MAPK family Omar A. Coso 1,Tamara Tanos1, Maria Julia Marinissen2, Lucrecia Poblitti1, J. Silvio Gutkind2 1 Laboratorio de Fisiología y Biología Molecular. Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina 2 Oral and Pharyngeal Cancer Branch. National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA Exposure of cells to sources of stress as well as to specific agonists that trigger cell proliferation induces a number of cellular alterations that are highly dependent on its ability to affect gene expression.Among them, the rapid activation of genes coding for two subfamilies of proto-oncoproteins, Fos and Jun, which constitute the AP-1 transcription factor, plays a key role in the subsequent regulation of expression of genes involved in DNA repair, cell proliferation, cell cycle arrest, death by apoptosis, and tissue and extracellular matrix remodeling proteases. Besides being regulated at the transcriptional level, Jun and Fos transcriptional activities are also regulated by phosphorylation as a result of the activation of intracellular signaling cascades. In this regard, the phosphorylation of c-Jun by activated JNK has been readily documented, whereas a role for Fos proteins and its putative Fos-activating kinases has remained elusive. Here we identify p38 MAPKs as proteins that can associate with c-Fos and phosphorylate its transactivation domain both in vitro and in vivo.This phosphorylation is transduced into changes in its transcriptional ability as p38-activated c-Fos enhances AP1-driven gene expression. Our findings indicate that as a consequence of the activation of pathways induced by UV light, among others, c-Fos becomes a substrate of p38 MAPKs, and provide, for the first time, evidence that support a critical role for p38 MAPKs in mediating c-Fos phosphorylation and gene transcription activation.Thus, this newly described pathways act concomitantly with the activation of c-Jun by JNK/MAPKs, thereby contributing to the complexity of AP1-driven gene transcription regulation.