UV-induced stabilization of c-fos and other short-lived mRNAs

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-f os is upregulated. This immediate induction is regulated nt the transcripti onal level and is transient in character, due to the autocatalyzed shutoff of transcription and the rapid turnover of c-fos mRNA. In an experiment ana lyzing the kinetics of c-fos mRNA expression in murine fibroblasts irradiat ed 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 irradia tion, 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 fr om about 10 to 60 min. With similar kinetics, the mRNAs of other UV target genes (i.e., the Kin17 gene, c-jun, I kappa B, 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 wit h an even greater accumulation of c-for and Kin17 mRNAs than repair-profici ent wild-type cells, suggesting that a process in which a repair protein is involved regulates mRNA stability. Although resembling the induction of p5 3, a DNA damage-dependent increase in p53 was not a necessary intermediate in the stabilization reaction, since cells derived from p53 knockout mice s howed the same pattern of c-fos and Kin17 mRNA accumulation as wild-type ce lls. The data indicate that the signal flow induced by UV radiation address es not only protein stability (p53) and transcription but also RNA stabilit y, a hitherto-unrecogoized level of UV-induced regulation.