Caspase-8-mediated PAR-4 cleavage is required for TNF?-induced apoptosis

Treude, Fabian; Kappes, Ferdinand; Fahrenkamp, Dirk; M�ller-Newen, Gerhard; Dajas-Bailador, Federico; Kr�mer, Oliver H.; L�scher, Bernhard; Hartkamp, J�rg

Abstract

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.

• Journal Article Type: Article
• Acceptance Date: Jan 27, 2014
• Publication Date: Jan 29, 2014
• Deposit Date: Jul 6, 2016
• Publicly Available Date: Jul 6, 2016
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 10
• DOI: https://doi.org/10.18632/oncotarget.1634
• Public URL: https://nottingham-repository.worktribe.com/output/721027
• Publisher URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=1634