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J. Biol. Chem., Vol. 279, Issue 2, 1010-1019, January 9, 2004

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Inhibition of Phosphatidylinositol 3-Kinase- and ERK MAPK-regulated Protein Synthesis Reveals the Pro-apoptotic Properties of CD40 Ligation in Carcinoma Cells^*

Clare C. Davies, Joanne Mason, Michael J. O. Wakelam, Lawrence S. Young, and Aristides G. Eliopoulos

From the Cancer Research United Kingdom Institute for Cancer Studies and Medical Research Council Centre for Immune Regulation, The University of Birmingham Medical School, Birmingham B15 2TA, United Kingdom

CD40, a member of the tumor necrosis factor receptor superfamily, is frequently expressed in carcinomas where its stimulation results in induction of apoptosis when de novo protein synthesis is inhibited. The requirement of protein synthesis inhibition for efficient killing suggests that CD40 transduces potent survival signals capable of suppressing its pro-apoptotic effects. We have found that inhibition of CD40 signaling on the phosphatidylinositol 3-kinase (PI3K) and ERK MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma cells to CD40-mediated cell death. The CD40-mediated PI3K and ERK activities were found to converge on the regulation of protein synthesis in carcinoma cells via a pathway involving the activation of p90 ribosomal S6 kinase (p90Rsk) and p70S6 kinases, upstream of the translation elongation factor eEF2. In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap-binding protein eIF4E as well as an ERK-dependent phosphorylation of eIF4E, thus promoting translation initiation. Concomitantly, the antiapoptotic protein cFLIP was found to be induced in CD40 ligand-stimulated carcinoma cells in a PI3K-, ERK-, and mammalian target of rapamycin (mTOR)-dependent manner and down-regulation of cFLIP_S expression sensitized to CD40-mediated carcinoma cell death. These data underline the significance of the PI3K and ERK pathways in controlling the balance between CD40-mediated survival and death signals through the regulation of the protein synthesis machinery. Pharmacological agents that target this machinery or its upstream kinases could, therefore, be exploited for CD40-based tumor therapy.

Received for publication, April 11, 2003 , and in revised form, October 27, 2003.

^* This work was supported by Cancer Research United Kingdom Grant SP2584 (to A. G. E. and L. S. Y.), a Biotechnology and Biological Sciences Research Council United Kingdom grant (to M. J. O. W.), and by a Medical Research Council (United Kingdom) Career Development Award (to A. G. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-121-414-2801; Fax: 44-121-414-3236; E-mail: A.G.Eliopoulos{at}bham.ac.uk.

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