Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis
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 functi...
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Impact Journals
2014
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| Online Access: | https://eprints.nottingham.ac.uk/34681/ |
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| author | Treude, Fabian Kappes, Ferdinand Fahrenkamp, Dirk Müller-Newen, Gerhard Dajas-Bailador, Federico Krämer, Oliver H. Lüscher, Bernhard Hartkamp, Jörg |
| author_facet | Treude, Fabian Kappes, Ferdinand Fahrenkamp, Dirk Müller-Newen, Gerhard Dajas-Bailador, Federico Krämer, Oliver H. Lüscher, Bernhard Hartkamp, Jörg |
| author_sort | Treude, Fabian |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:23:42Z |
| format | Article |
| id | nottingham-34681 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:23:42Z |
| publishDate | 2014 |
| publisher | Impact Journals |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-346812020-05-04T16:41:14Z https://eprints.nottingham.ac.uk/34681/ 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 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. Impact Journals 2014-01-29 Article PeerReviewed Treude, Fabian, Kappes, Ferdinand, Fahrenkamp, Dirk, Müller-Newen, Gerhard, Dajas-Bailador, Federico, Krämer, Oliver H., 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 http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=1634 doi:10.18632/oncotarget.1634 doi:10.18632/oncotarget.1634 |
| spellingShingle | Treude, Fabian Kappes, Ferdinand Fahrenkamp, Dirk Müller-Newen, Gerhard Dajas-Bailador, Federico Krämer, Oliver H. Lüscher, Bernhard Hartkamp, Jörg Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title | Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title_full | Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title_fullStr | Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title_full_unstemmed | Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title_short | Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis |
| title_sort | caspase-8-mediated par-4 cleavage is required for tnfα-induced apoptosis |
| url | https://eprints.nottingham.ac.uk/34681/ https://eprints.nottingham.ac.uk/34681/ https://eprints.nottingham.ac.uk/34681/ |