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Marivin A.,French Institute of Health and Medical Research | Marivin A.,University of Burgundy | Berthelet J.,French Institute of Health and Medical Research | Berthelet J.,University of Burgundy | And 14 more authors.
Oncogene | Year: 2013

Tumour necrosis factor-α (TNF) is a cytokine endowed with multiple functions, depending on the cellular and environmental context. TNF receptor engagement induces the formation of a multimolecular complex including the TNFR-associated factor TRAF2, the receptor-interaction protein kinase RIP1 and the cellular inhibitor of apoptosis cIAP1, the latter being essential for NF-κB activation. Here, we show that cIAP1 also regulates TNF-induced actin cytoskeleton reorganization through a cdc42-dependent, NF-κB-independent pathway. Deletion of cIAP1 prevents TNF-induced filopodia and cdc42 activation. The expression of cIAP1 or its E3-ubiquitin ligase-defective mutant restores the ability of cIAP1-/- MEFs to produce filopodia, whereas a cIAP1 mutant unable to bind TRAF2 does not. Accordingly, the silencing of TRAF2 inhibits TNF-mediated filopodia formation, whereas silencing of RIP1 does not. cIAP1 directly binds cdc42 and promotes its RhoGDIα-mediated stabilization. TNF decreases cIAP1-cdc42 interaction, suggesting that TNF-induced recruitment of cIAP1/TRAF2 to the receptor releases cdc42, which in turn triggers actin remodeling. cIAP1 also regulates cdc42 activation in response to EGF and HRas-V12 expression. A downregulation of cIAP1 altered the cell polarization, the cell adhesion to endothelial cells and cell intercalation, which are cdc42-dependent processes. Finally, we demonstrated that the deletion of cIAP1 regulated the HRas-V12-mediated transformation process, including anchorage-dependent cell growth, tumour growth in a xenograft model and the development of experimental metastasis in the lung.Oncogene advance online publication, 25 November 2013; doi:10.1038/onc.2013.499. Source

Cartier J.,University of Burgundy | Cartier J.,Institute Federatif Of Recherche Ifr 100 | Marivin A.,University of Burgundy | Marivin A.,Institute Federatif Of Recherche Ifr 100 | And 4 more authors.
Medecine/Sciences | Year: 2012

The function of IAP has long been limited to an inhibition of apoptosis through their capacity to bind some caspases. Since the expression of these proteins is altered in some tumor samples, lAPs are targets for anticancer therapy and many small molecules have been designed for their capacity to inhibit lAP-caspase interaction. Unexpectedly, these molecules appeared to significantly affect NF-κB activation. In this review, we will discuss the central role of clAPl, clAP2 and XIAP in the regulation of NF-κB activating signaling pathways. Source

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