TRANSACTIVATION OF C-FOS AND BETA-ACTIN GENES BY RAF AS A STEP IN EARLY RESPONSE TO TRANSMEMBRANE SIGNALS

A primary response to many growth factor-induced trans-membrane signals is the rapid activation of transcription of the proto-oncogene c-fos and other early-response genes, including the β-actin gene1,2. The c-raf gene encodes a cytoplasmic serine/threonine kinase, raf-1 (réf. 3), whose activity is also respon-sive to transmembrane signals4,5 and which in mutant form can transform cells6. Here we show that in transient assays, the v-raf protein, which is a constitutively activated oncogenic counterpart of raf-1, can transactivate transcription from two early-response promoters, including the c-fos promoter from human and murine cells and the human β-actin gene promoter. Multiple elements of the human fos promoter, including the dyad symmetry element necessary for growth-factor induction, an octanucleotide direct repeat element, and the region spanning the sequence from nucleo-tides -225 to -99 can all serve as targets for raf induction. The c-myc promoter and two adenovirus-2 early promoters are not induced. These findings indicate that raf kinase, when activated by a transmembrane signal or by mutation of a regulatory domain, can phosphorylate a factor(s) capable of regulating transcription of the c-fos and actin genes. The oncogenic form of raf may transform by constitutively activating early response proto-oncogenes such as c-fos. © 1990 Nature Publishing Group.