Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis
Treude, Fabian and Kappes, Ferdinand and Fahrenkamp, Dirk and Müller-Newen, Gerhard and Dajas-Bailador, Federico and Krämer, Oliver H. and Lüscher, Bernhard and Hartkamp, Jörg (2014) Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis. Oncotarget, 5 (10). pp. 2988-2998. ISSN 1949-2553
Official URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=1634
The tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a subset of human cancers and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is currently unknown. We demonstrate here that UV-induced apoptosis results in a rapid caspase-dependent PAR-4 cleavage at EEPD131¯G, a sequence that was preferentially recognized by caspase-8. To investigate the effect on cell growth for this cleavage event we established stable cell lines that express wild-type-PAR-4 or the caspase cleavage resistant mutant PAR-4 D131G under the control of a doxycycline-inducible promoter. Induction of the wild-type protein but not the mutant interfered with cell proliferation, predominantly through induction of apoptosis. We further demonstrate that TNFα-induced apoptosis leads to caspase-8-dependent PAR-4-cleavage followed by nuclear accumulation of the C-terminal PAR-4 (132-340) fragment, which then induces apoptosis. Taken together, our results indicate that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by caspase-8.
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