title: Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA.
abstract: Inhibition of protein synthesis per se does not potentiate the stress-activated protein kinases (SAPKs; also known as cJun NH2-terminal kinases [JNKs]). The protein synthesis inhibitor anisomycin, however, is a potent activator of SAPKs/JNKs. The mechanism of this activation is unknown. We provide evidence that in order to activate SAPK/JNK1, anisomycin requires ribosomes that are translationally active at the time of contact with the drug, suggesting a ribosomal origin of the anisomycin-induced signaling to SAPK/JNK1. In support of this notion, we have found that aminohexose pyrimidine nucleoside antibiotics, which bind to the same region in the 28S rRNA that is the target site for anisomycin, are also potent activators of SAPK/JNK1. Binding of an antibiotic to the 28S rRNA interferes with the functioning of the molecule by altering the structural interactions of critical regions. We hypothesized, therefore, that such alterations in the 28S rRNA may act as recognition signals to activate SAPK/JNK1. To test this hypothesis, we made use of two ribotoxic enzymes, ricin A chain and alpha-sarcin, both of which catalyze sequence-specific RNA damage in the 28S rRNA. Consistent with our hypothesis, ricin A chain and alpha-sarcin were strong agonists of SAPK/JNK1 and of its activator SEK1/MKK4 and induced the expression of the immediate-early genes c-fos and c-jun. As in the case of anisomycin, ribosomes that were active at the time of exposure to ricin A chain or alpha-sarcin were able to initiate signal transduction from the damaged 28S rRNA to SAPK/JNK1 while inactive ribosomes were not.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Iordanov
authors.forename: D
authors.initials: D
authors.lastname: Pribnow
authors.forename: J L
authors.initials: JL
authors.lastname: Magun
authors.forename: T H
authors.initials: TH
authors.lastname: Dinh
authors.forename: J A
authors.initials: JA
authors.lastname: Pearson
authors.forename: S L
authors.initials: SL
authors.lastname: Chen
authors.forename: B E
authors.initials: BE
authors.lastname: Magun
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005656:Fungal Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000378:metabolism; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors*; D011494:Protein Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012339:RNA, Ribosomal, 28S / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D012270:Ribosomes / Q000378:metabolism*; D012276:Ricin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D009705:Nucleosides; D011500:Protein Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012339:RNA, Ribosomal, 28S; C014801:alpha-sarcin; D000841:Anisomycin; C004500:blasticidin S; D012276:Ricin; D010458:Peptidyl Transferases; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004722:Endoribonucleases