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J. Biol. Chem., Vol. 276, Issue 9, 6280-6288, March 2, 2001

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Ras Controls Tumor Necrosis Factor Receptor-associated Factor (TRAF)6-dependent Induction of Nuclear Factor-B
SELECTIVE REGULATION THROUGH RECEPTOR SIGNALING COMPONENTS^*

Christopher J. Caunt, Endré Kiss-Toth, Franco Carlotti, Robert Chapman, and Eva E. Qwarnstrom^§¶

From the  Functional Genomics, Division of Molecular and Genetic Medicine, University of Sheffield, S10 2JF, United Kingdom and the ^§ Department of Pathology, School of Medicine, University of Washington, Seattle, Washington 98195

In the present study, we show that Ras activity differentially controls interleukin (IL)-1 induced transcription factor activation by selective regulation of responses mediated by receptor complex components. Initial experiments revealed that stimulation with IL-1 caused a rapid, matrix-dependent activation of Ras. The effect was transient, peaking at 5 min and returning to base levels after 30 min. Activation correlated with pronounced changes in cell shape in EGFPH-Ras transfected cells. Transfection with the dominant negative mutant, Ras^Asn-17, inhibited IL-1 induced activation of the IL-8 promoter as well as of NF-B and AP-1 synthetic promoters in transient transfection assays. Furthermore, overexpression of the IL-1 signaling proteins TRAF6 or MyD88 gave characteristic activation of IL-8, which was accentuated in the presence of IL-1. Co-transfection with Ras^Asn-17 gave a dose-dependent inhibition of TRAF6-induced responses in the presence and absence of IL-1, but had no effect on MyD88 mediated activity. Similarly, induction of NF-B was abolished by Ras^Asn-17 only in TRAF6-transfected cells. In contrast, inhibiting Ras activity limited AP-1-mediated responses through both receptor complex proteins. Constitutively active Ras^Val-12 increased the TRAF6 induced activity of the NF-B pathway similar to the effect induced by IL-1, while the Ras^Val-12 induced activity was not inhibited by co-transfection with a dominant negative TRAF6. Our data show that activation of the Ras GTPase is an early, matrix-dependent response in IL-1 signaling which participates in structural regulation of IL-1-induced genes. In addition, they show that the Ras induced effect selectively regulates TRAF6-mediated activation of the NF-B pathway, suggesting that Ras GTPase represents a convergence point in structural and cytokine responses, with distinct effects on a subset of downstream signaling events.

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