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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

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


Fabian Treude

Ferdinand Kappes

Dirk Fahrenkamp

Gerhard M�ller-Newen

Oliver H. Kr�mer

Bernhard L�scher

J�rg Hartkamp


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.


Treude, F., Kappes, F., Fahrenkamp, D., Müller-Newen, G., Dajas-Bailador, F., Krämer, O. H., …Hartkamp, J. (2014). Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis. Oncotarget, 5(10),

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
Public URL
Publisher URL


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