Oncotarget

Research Papers:

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

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

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Oncotarget. 2014; 5:2988-2998. https://doi.org/10.18632/oncotarget.1634

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Abstract

Fabian Treude1, Ferdinand Kappes1, Dirk Fahrenkamp1, Gerhard Müller-Newen1, Federico Dajas-Bailador2, Oliver H. Krämer3, Bernhard Lüscher1, Jörg Hartkamp1

1 Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany

2 Faculty of Medicine and Health Sciences, Queens Medical Centre, University of Nottingham, Nottingham, U.K.

3 Institute of Toxicology, University Medical Center Mainz, Mainz, Germany

Correspondence:

Jörg Hartkamp, email:

Keywords: PAR-4, apoptosis, caspase-8, tumor suppressor, TNFα

Received: November 27, 2013 Accepted: January 27, 2014 Published: January 29, 2014

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.


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