Raf-induced transformation requires an interleukin 1 autocrine loop

The c-Raf-1 serine/threonine protein kinase plays a critical role in the pr oliferation of most cell types that have been examined. As such, the Raf pr oto-oncogene Is thought to play a central role in the development of human tumors. Although the c-mf-1 gene itself rarely appears to be mutated in hum an tumors, the kinase activity of Raf is frequently found to be more active in tumor cells, likely through constitutive activation of upstream activat ors of Raf, The downstream events triggered by Raf that are involved in tra nsformation have been studied less extensively. We show in this study that Raf-induced transformation of NIH 3T3 cells requires the activation of the ubiquitously expressed transcription factor, nuclear faetor-kappaB, by Raf, Furthermore, through the use of CrmA, interleukin 1 (IL-1) receptor antago nist, and a dominant-negative form of TRAF6, we demonstrate a requirement f or IL-1 production and signaling from the IL-1 receptor as necessary compon ents of Raf-induced transformation. These results indicate that IL-1 may be used as an autocrine growth factor by a number of tumors in which activati on of Raf plays an important role in transformation and suggest that blocka de of IL-1 signaling may be an approach to limiting the growth of certain t umors.