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Molecular and Cellular Biology, May 2000, p. 3616-3625, Vol. 20, No. 10
Forschungszentrum Karlsruhe, Institute of
Toxicology and Genetics,1 and University
of Karlsruhe, Institute of Genetics,3 76021 Karlsruhe, Germany, and Laboratoire de Génétique de
la Radiosensibilité, Département de Radiobiologie et de
Radiopathologie, Direction des Sciences du Vivant, Commissariat a
l'Energie Atomique, CEFAR, 92265 Fontenay-aux-Roses,
France2
Received 20 August 1999/Returned for modification 18 October
1999/Accepted 28 February 2000
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, I
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
UV-Induced Stabilization of c-fos and
Other Short-Lived mRNAs
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 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.
*
Corresponding author. Mailing address:
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O.
Box 3640, 76021 Karlsruhe, Germany. Phone: 49-7247-823292. Fax:
49-7247-823354. E-mail: genetik{at}igen.fzk.de.
Present address: Cancer Research Campaign, Cell Transformation
Research Group, Department of Biochemistry, Medical Sciences Institute,
University of Dundee, Dundee DD1 4HN, United Kingdom.
Present address: Medical Research Council, Cell Mutation Unit,
Sussex University, Falmer, Brighton BN1 9RR, United Kingdom.
§
Present address: Institut für Rechtsmedizin, Am Pulverturm 3, 55131 Mainz, Germany.
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