| First Author | Pietkiewicz S | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 4 | Pages | e61438 |
| PubMed ID | 23593480 | Mgi Jnum | J:200024 |
| Mgi Id | MGI:5506837 | Doi | 10.1371/journal.pone.0061438 |
| Citation | Pietkiewicz S, et al. (2013) Oppositional regulation of Noxa by JNK1 and JNK2 during apoptosis induced by proteasomal inhibitors. PLoS One 8(4):e61438 |
| abstractText | 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, HIF1alpha, 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. |
