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Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors

Proteasome inhibitors (PIs) potently induce apoptosis in a variety of tumor cells, but the underlying mechanisms are not fully elucidated. Comparing PI-induced apoptosis susceptibilities of various mouse embryonic fibroblast (MEF) lines differing in their c-jun N-terminal kinase (JNK) 1 and 2 status...

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Autores principales: Pietkiewicz, Sabine, Sohn, Dennis, Piekorz, Roland P., Grether-Beck, Susanne, Budach, Wilfried, Sabapathy, Kanaga, Jänicke, Reiner U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623862/
https://www.ncbi.nlm.nih.gov/pubmed/23593480
http://dx.doi.org/10.1371/journal.pone.0061438
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author Pietkiewicz, Sabine
Sohn, Dennis
Piekorz, Roland P.
Grether-Beck, Susanne
Budach, Wilfried
Sabapathy, Kanaga
Jänicke, Reiner U.
author_facet Pietkiewicz, Sabine
Sohn, Dennis
Piekorz, Roland P.
Grether-Beck, Susanne
Budach, Wilfried
Sabapathy, Kanaga
Jänicke, Reiner U.
author_sort Pietkiewicz, Sabine
collection PubMed
description Proteasome inhibitors (PIs) potently induce apoptosis in a variety of tumor cells, but the underlying mechanisms are not fully elucidated. Comparing PI-induced apoptosis susceptibilities of various mouse embryonic fibroblast (MEF) lines differing in their c-jun N-terminal kinase (JNK) 1 and 2 status, we show that several hallmarks of apoptosis were most rapidly detectable in JNK2−/− cells, whereas they appeared only delayed and severely reduced in their intensities in cells expressing JNK2. Consistent with our finding that PI-induced apoptosis requires de novo protein synthesis, the proteasomal inhibitor MG-132 induced expression of the BH3-only protein Noxa at the transcriptional level in a JNK1-dependent, but JNK2-opposing manner. As the knockdown of Noxa blocked only the rapid PI-induced apoptosis of JNK2−/− cells, but not the delayed death occurring in JNK1−/− and JNK1+/+ cells, our data uncover a novel PI-induced apoptosis pathway that is regulated by the JNK1/2-dependent expression of Noxa. Furthermore, several transcription factors known to modulate Noxa expression including ATF3, ATF4, c-Jun, c-Myc, HIF1α, and p53 were found upregulated following MG-132 exposure. From those, only knockdown of c-Myc rescued JNK2−/− cells from PI-induced apoptosis, however, without affecting expression of Noxa. Together, our data not only show that a rapid execution of PI-induced apoptosis requires JNK1 for upregulation of Noxa via an as yet unknown transcription factor, but also that JNK2 controls this event in an oppositional manner.
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spelling pubmed-36238622013-04-16 Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors Pietkiewicz, Sabine Sohn, Dennis Piekorz, Roland P. Grether-Beck, Susanne Budach, Wilfried Sabapathy, Kanaga Jänicke, Reiner U. PLoS One Research Article Proteasome inhibitors (PIs) potently induce apoptosis in a variety of tumor cells, but the underlying mechanisms are not fully elucidated. Comparing PI-induced apoptosis susceptibilities of various mouse embryonic fibroblast (MEF) lines differing in their c-jun N-terminal kinase (JNK) 1 and 2 status, we show that several hallmarks of apoptosis were most rapidly detectable in JNK2−/− cells, whereas they appeared only delayed and severely reduced in their intensities in cells expressing JNK2. Consistent with our finding that PI-induced apoptosis requires de novo protein synthesis, the proteasomal inhibitor MG-132 induced expression of the BH3-only protein Noxa at the transcriptional level in a JNK1-dependent, but JNK2-opposing manner. As the knockdown of Noxa blocked only the rapid PI-induced apoptosis of JNK2−/− cells, but not the delayed death occurring in JNK1−/− and JNK1+/+ cells, our data uncover a novel PI-induced apoptosis pathway that is regulated by the JNK1/2-dependent expression of Noxa. Furthermore, several transcription factors known to modulate Noxa expression including ATF3, ATF4, c-Jun, c-Myc, HIF1α, and p53 were found upregulated following MG-132 exposure. From those, only knockdown of c-Myc rescued JNK2−/− cells from PI-induced apoptosis, however, without affecting expression of Noxa. Together, our data not only show that a rapid execution of PI-induced apoptosis requires JNK1 for upregulation of Noxa via an as yet unknown transcription factor, but also that JNK2 controls this event in an oppositional manner. Public Library of Science 2013-04-11 /pmc/articles/PMC3623862/ /pubmed/23593480 http://dx.doi.org/10.1371/journal.pone.0061438 Text en © 2013 Pietkiewicz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pietkiewicz, Sabine
Sohn, Dennis
Piekorz, Roland P.
Grether-Beck, Susanne
Budach, Wilfried
Sabapathy, Kanaga
Jänicke, Reiner U.
Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title_full Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title_fullStr Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title_full_unstemmed Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title_short Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors
title_sort oppositional regulation of noxa by jnk1 and jnk2 during apoptosis induced by proteasomal inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623862/
https://www.ncbi.nlm.nih.gov/pubmed/23593480
http://dx.doi.org/10.1371/journal.pone.0061438
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