KAPPA-B SITE-DEPENDENT INDUCTION OF GENE-EXPRESSION BY DIVERSE INDUCERS OF NUCLEAR FACTOR-KAPPA-B REQUIRES RAF-1

The transcription factor nuclear factor kappaB (NF-kappaB) is sequeste red in the cytoplasm of most cell types where it is complexed with its inhibitor (IkappaB). A large variety of agents, including growth fact ors, the tumor promoter phorbol 12-myristate 13-acetate, and the cytok ine tumor necrosis factor alpha, initiate signal transduction pathways that converge upon the NF-kappaB.IkappaB complex, resulting in the di ssociation of IkappaB and the translocation of NF-kappaB to the nucleu s. It has been demonstrated that the phosphorylation of IkappaB is ass ociated with NF-kappaB activation, although the kinase(s) responsible for this process in vivo remain unknown. Here we demonstrate that expr ession of activated forms of the GTP-binding protein Ras or of the ser ine/threonine kinase Raf-1 results in the activation of transcription specifically through kappaB sites. This activation appears to be depen dent on NF-kappaB, since co-expression of IkappaBalpha eliminates both Ras- and Raf-1-induced transcription. In addition, through the use of a dominant negative form of Raf-1, we show that Raf-I is a common com ponent utilized by multiple inducers in kappaB site-driven gene expres sion. These results illuminate a signal transduction pathway in which NF-kappaB/Rel family members participate and also implicate a pathway responsible for kappaB site-dependent gene expression during cell grow th and in immune and inflammatory responses.