Ultraviolet radiation triggers the ribotoxic stress response in mammalian cells.
The ribotoxic stress response, which is conserved between prokaryotes and eukaryotes, is a cellular reaction to cytotoxic interference with the function of the 3'-end of the large (23 S/28 S) ribosomal RNA. The 3'-end of the large rRNA is directly involved in the three sequential steps of translational elongation: the aminoacyl-tRNA binding, the peptidyl transfer, and the ribosomal translocation. In mammalian cells, the ribotoxic stress response involves activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase and the p38 mitogen-activated protein kinase and transcriptional induction of immediate early genes such as c-fos and c-jun. Active ribosomes are essential mediators of the ribotoxic stress response. We demonstrate here that the transcriptional response of mammalian cells to ultraviolet radiation (UV response) displays the characteristics of a ribotoxic stress response, inasmuch as (i) the activation of stress kinases and gene expression in response to UV requires the presence of active ribosomes at the moment of irradiation; (ii) UV irradiation inhibits protein synthesis; and (iii) irradiation of cells with UV causes specific damage to the 3'-end of the 28 S rRNA. In contrast, the activation of the stress kinases by hyperosmolarity, by the DNA-cross-linking agent diepoxybutane, or by growth factors and cytokines does not depend on the presence of active ribosomes. Our results identify UV as a potential ribotoxic stressor and support the notion that some of the cellular signaling cascades in response to UV might be generated in the ribosome, possibly triggered by damage to rRNA.
Iordanov
M S
MS
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Pribnow
D
D
Magun
J L
JL
Dinh
T H
TH
Pearson
J A
JA
Magun
B E
BE
D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D005656:Fungal Proteins; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012339:RNA, Ribosomal, 28S / Q000378:metabolism / Q000528:radiation effects*; D051381:Rats; D013312:Stress, Physiological / Q000503:physiopathology*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D005656:Fungal Proteins; D012339:RNA, Ribosomal, 28S; C014801:alpha-sarcin; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D004722:Endoribonucleases