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Papers In Press, published online ahead of print November 15, 2000
Genomic Medicine, University of Sheffield Medical School, Sheffield, South Yorkshire S10 2JF
Corresponding Author: E.Qwarnstrom{at}Sheffield.ac.uk
In the present study, we show that Ras activity differentially controls 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 minutes and returning to base levels after 30 minutes. Activation correlated with pronounced changes in cell shape in EGFPH-Ras transfected cells. Transfection with the dominant negative mutant, N17Ras, inhibited IL-1 induced activation of the IL-8 promoter as well as of NF-kB and AP-1 synthetic promoters in transient transfection assays. Further, over-expression of the IL-1 signalling proteins TRAF6 or MyD88 gave characteristic activation of IL-8, which was accentuated in the presence of IL-1. Co-transfection with N17Ras 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-kB was abolished by N17Ras only in TRAF6 transfected cells. In contrast, inhibiting Ras activity limited AP-1 mediated responses through both receptor complex proteins. Constitutively active V12Ras increased the TRAF6 induced activity of the NF-kB pathway similar to the effect induced by IL-1, while the V12Ras 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 signalling 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-kB pathway, suggesting that the Ras GTPase represents a convergence point in structural and cytokine responses, with distinct effects on a subset of downstream signalling events.
J. Biol. Chem, 10.1074/jbc.M006772200
Submitted on July 28, 2000
Revised on October 3, 2000
Accepted on November 14, 2000
Ras controls TRAF6 dependent induction of NF-kappaB - selective regulation through receptor signalling components
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