title: UV-Induced stabilization of c-fos and other short-lived mRNAs.
abstract: Irradiation of cells with short-wavelength ultraviolet light (UVC) changes the program of gene expression, in part within less than 15 min. As one of the immediate-early genes in response to UV, expression of the oncogene c-fos is upregulated. This immediate induction is regulated at the transcriptional level and is transient in character, due to the autocatalyzed shutoff of transcription and the rapid turnover of c-fos mRNA. In an experiment analyzing the kinetics of c-fos mRNA expression in murine fibroblasts irradiated with UVC, we found that, in addition to the initial transient induction, c-fos mRNA accumulated in a second wave starting at 4 to 5 h after irradiation, reaching a maximum at 8 h, and persisting for several more hours. It was accompanied by an increase in Fos protein synthesis. The second peak of c-fos RNA was caused by an UV dose-dependent increase in mRNA half-life from about 10 to 60 min. With similar kinetics, the mRNAs of other UV target genes (i.e., the Kin17 gene, c-jun, IkappaB, and c-myc) were stabilized (e.g., Kin17 RNA from 80 min to more than 8 h). The delayed response was not due to autocrine cytokine secretion with subsequent autostimulation of the secreting cells or to UV-induced growth factor receptor activation. Cells unable to repair UVC-induced DNA damage responded to lower doses of UVC with an even greater accumulation of c-fos and Kin17 mRNAs than repair-proficient wild-type cells, suggesting that a process in which a repair protein is involved regulates mRNA stability. Although resembling the induction of p53, a DNA damage-dependent increase in p53 was not a necessary intermediate in the stabilization reaction, since cells derived from p53 knockout mice showed the same pattern of c-fos and Kin17 mRNA accumulation as wild-type cells. The data indicate that the signal flow induced by UV radiation addresses not only protein stability (p53) and transcription but also RNA stability, a hitherto-unrecognized level of UV-induced regulation.
authors.affiliation: Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Blattner
authors.forename: P
authors.initials: P
authors.lastname: Kannouche
authors.forename: M
authors.initials: M
authors.lastname: Litfin
authors.forename: K
authors.initials: K
authors.lastname: Bender
authors.forename: H J
authors.initials: HJ
authors.lastname: Rahmsdorf
authors.forename: J F
authors.initials: JF
authors.lastname: Angulo
authors.forename: P
authors.initials: P
authors.lastname: Herrlich
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D017781:Genes, Immediate-Early / Q000528:radiation effects; D016762:Genes, fos / Q000528:radiation effects; D016158:Genes, p53; D006207:Half-Life; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D020871:RNA Stability / Q000528:radiation effects*; D012333:RNA, Messenger / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D018808:Transcription Factor AP-1; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020794:Receptor Protein-Tyrosine Kinases