title: Oppositional regulation of Noxa by JNK1 and JNK2 during apoptosis induced by proteasomal inhibitors.
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.
authors.affiliation: Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pietkiewicz
authors.forename: Dennis
authors.initials: D
authors.lastname: Sohn
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.forename: Susanne
authors.initials: S
authors.lastname: Grether-Beck
authors.forename: Wilfried
authors.initials: W
authors.lastname: Budach
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
authors.forename: Reiner U
authors.initials: RU
authors.lastname: Jänicke
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D005470:Fluorometry; D005786:Gene Expression Regulation / Q000502:physiology*; D055786:Gene Knockout Techniques; D007976:Leupeptins; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D007976:Leupeptins; C408009:Pmaip1 protein, mouse; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde