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* Department of Molecular Biology and Biochemistry, and Center for Immunology, University of California, Irvine, CA 92697;
Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892;
Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892; and
Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of California, Irvine, CA 92697
Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.
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1 This work was supported by National Institutes of Health Grant AI050606 (to C.M.W.) and Training Grants T32GM007311, T32CA09054, and T32AI060573 (to A.F.A., B.D.B., and S.J.R., respectively).
2 Current address: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.
3 Address correspondence and reprint requests to Dr. Craig M. Walsh, Department of Molecular Biology and Biochemistry, and Center for Immunology, University of California, Irvine, CA 92697-3900. E-mail address: cwalsh{at}uci.edu
4 Abbreviations used in this paper: FADD, Fas-associated death domain protein; DD, death domain protein; FADDdd, dominant-negative form of FADD; v-FLIP, viral FLIP; S6K, S6 kinase; CDK, cyclin-dependent kinase; Rap, rapamycin; mTOR, mammalian target of Rap; Rb, retinoblastoma; Rosc, roscovitine; ChIP, chromatin immunoprecipitation; 7AAD, 7-aminoactinomycin D; SGK, serum and glucocorticoid-regulated kinase.
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