Signaling pathways leading to transcription and translation cooperatively regulate the transient increase in expression of c-Fos protein

The mechanisms by which growth factors trigger signal transduction pathways leading to the regulation of c-Fos expression are of great interest. in th is study we investigated the effect of hepatocyte growth factor (HGF/SF) an d epidermal growth factor (EGF) on the expression of c-fos and its product, c-Fos, in human epithelial cell line MKN74, The expression level of c-Fos protein in HGF/SF-stimulated cells was 5-10-fold higher than that in EGF-st imulated cells, whereas the level of c-fos mRNA induced by HGF/SF was simil ar to that by EGF, The hyperphosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), indicative of an increased number of transl ation initiation complexes, was detected only in HGF/SF-induced MKN74 cells . Activation of phosphatidylinositol-3 ' -OH kinase and FKBP12-rapamycin as sociated mammalian target of rapamycin (FRAP/mTOR) was observed after the t reatment with HGF/SF, Pretreatment with an inhibitor of either one, i.e. LY 294002 for phosphatidylinositol-3 ' -OH kinase or rapamycin for FRAP/mTOR, completely inhibited 4E-BP1 phosphorylation and decreased the c-Fos synthes is induced by HGF/SF down to the level found in EGF-induced cells. These re sults suggest that the phosphorylation of 4E-BP1 is stimulated by HGF/SF in a manner requiring both phosphatidy-linositol-3 ' -OH kinase-dependent and FRAP/mTOR-dependent pathways, thereby stimulating c-fos mRNA translation. Regulation of the translation process of c-fos mRNA in addition to the imme diate activation of c-fos transcription is necessary for the transient incr ease in the level of c-Fos protein to stimulate cell proliferation.