Research Repository

See what's under the surface

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

Treude, Fabian; Kappes, Ferdinand; Fahrenkamp, Dirk; Müller-Newen, Gerhard; Dajas-Bailador, Federico; Krämer, Oliver H.; Lüscher, Bernhard; Hartkamp, Jörg

Authors

Fabian Treude

Ferdinand Kappes

Dirk Fahrenkamp

Gerhard Müller-Newen

Federico Dajas-Bailador

Oliver H. Krämer

Bernhard Lüscher

Jörg Hartkamp

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
Publication Date Jan 29, 2014
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 5
Issue 10
Institution Citation 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), doi:10.18632/oncotarget.1634
DOI https://doi.org/10.18632/oncotarget.1634
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=1634
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

1634-17335-3-PB.pdf (1.7 Mb)
PDF

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0




Downloadable Citations