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Caspase-8-Dependent HER-2 Cleavage in Response to Tumor Necrosis Factor Stimulation Is Counteracted by Nuclear Factor B through c-FLIP-L Expression

¹ Laboratory of Medical Chemistry and Human Genetics, Center for Molecular and Cellular Therapy and ² Center for Research in Experimental Cancerology, University of Liege, Liege, Belgium

The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor (TNF-) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor B (NFB) activation. We show that the antiapoptotic transcription factor NFB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF--induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFB-defective cells against TNF--mediated cell death. Therefore, we propose an original model in which NFB exerts a new antiapoptotic function by counteracting TNF--triggered cleavage of the HER-2 survival factor.

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