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• W2023120046 endingPage "e61438" @default.
• W2023120046 startingPage "e61438" @default.
• W2023120046 abstract "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." @default.
• W2023120046 created "2016-06-24" @default.
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• W2023120046 date "2013-04-11" @default.
• W2023120046 modified "2023-10-17" @default.
• W2023120046 title "Oppositional Regulation of Noxa by JNK1 and JNK2 during Apoptosis Induced by Proteasomal Inhibitors" @default.
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• W2023120046 doi "https://doi.org/10.1371/journal.pone.0061438" @default.
• W2023120046 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3623862" @default.
• W2023120046 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23593480" @default.
• W2023120046 hasPublicationYear "2013" @default.
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