Signaling pathways involved in c-fos mRNA stability.

MARIA SOL DEGESE; TAMARA B. TANOS; JULIAN NAIPAUER; NATALIA ALONSO; FEDERICO COLUCCIO LESKOW; OMAR A. COSO

Bariloche ARGENTINA

Congreso; Combined meetings on Gene Expresión and Rna processing.; 2007

Living cells react to extracellular signals in a variety of responses that include gene expression regulation. Kinase cascades play a key role in the modulation of those responses. Phosphorylation of transcription factors that trigger promoter activity and increase mRNA levels in response to extracellular signals is well characterized. AP-1 family genes as c-jun or c-fos are representative early responsive genes and the subject of such regulation. MAPKs (Erk1/2 and SAPKs) comprise a family of serine/threonine protein kinases that phosphorylate transcription factors including members of AP-1.    In the signal transduction field the ways activating biochemical processes inside the cell are activated are far better known than the corresponding inactivating events that might eventually follow. We have been studying the influence of signal transduction pathways upon mRNA and protein expression for years and lately we have focused on c-Fos. We have observed that c-Fos mRNA levels peak shortly after cells are stimulated with growth factors and sharply decrease afterwards. While the first event is now well characterized, little is known about the molecular mechanisms that control the latter. Certain proteins known collectively as AUBPs bind to specific motifs (AREs) in the 3’ untranslated region of messenger RNAs changing its stability. Some of the proteins that bind to the 3’UTR of c-Fos have been described and we have identified them as potential targets for MAPK phosphorylation. We have subcloned the c-fos 3’UTR into a reporter vector downstream of a CMV driven luciferase gene. We have observed that stability of both this luciferase mRNA and endogenous c-fos mRNA is strictly dependent on SAPK activity. As has been extensively described for mRNA production and recently for RNA processing, we understand that mRNA stability is regulated by proteins that bind to sequence specific motifs in nucleic acids, and have their activities regulated by signaling cascades. We are characterizing the molecular events involved using c-fos as a model gene.