Raf-induced transformation requires an interleukin 1 autocrine loop.
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-kappaB, 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.
Vale
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Department of Internal Medicine and Harold C Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235-8884, USA.
Ngo
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White
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MA
Lipsky
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PE
D016475:3T3 Cells; D000818:Animals; D019898:Autocrine Communication; D002471:Cell Transformation, Neoplastic; D004274:DNA, Recombinant; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
D004274:DNA, Recombinant; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D012795:Sialoglycoproteins; D019908:Proto-Oncogene Proteins c-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins