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Raf-induced Transformation Requires an Interleukin 1 Autocrine Loop

Department of Internal Medicine and Harold C. Simmons Arthritis Research Center [T. V., P. E. L.], and Department of Cell Biology and Neuroscience [T. T. N., M. A. W.], University of Texas Southwestern Medical Center, Dallas, Texas 75235-8884

The c-Raf-1 serine/threonine protein kinase plays a critical role in the proliferation of most cell types that have been examined. As such, the Raf proto-oncogene is thought to play a central role in the development of human tumors. Although the c-raf-1 gene itself rarely appears to be mutated in human tumors, the kinase activity of Raf is frequently found to be more active in tumor cells, likely through constitutive activation of upstream activators of Raf. The downstream events triggered by Raf that are involved in transformation 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 factor-B, by Raf. Furthermore, through the use of CrmA, interleukin 1 (IL-1) receptor antagonist, and a dominant-negative form of TRAF6, we demonstrate a requirement for IL-1 production and signaling from the IL-1 receptor as necessary components 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 activation of Raf plays an important role in transformation and suggest that blockade of IL-1 signaling may be an approach to limiting the growth of certain tumors.

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