Defects in transcription coupled repair interfere with expression of p90(MDM2) in response to ultraviolet light.
Ultraviolet (UV) irradiation transiently stabilizes p53 through a mechanism that may require a decrease in the activity of the ubiquitin ligase, p90(MDM2). Conversely, the recovery of low levels of p53 following UV exposure may depend on an increase in p90(MDM2). The level of p90(MDM2) is increased by UV light following the p53-dependent induction of an internal mdm2 promoter, P2. If this induction of mdm2 were critical for the recovery of low levels of p53 following UV exposure, defects in mdm2's transcription would result in a prolonged increase in p53. Cells defective in transcription coupled repair (TCR) maintain high levels of p53 for a prolonged period following UV exposure. Such cells also have defects in general transcription after UV irradiation. We investigated whether TCR-deficient cells express diminished levels of mdm2 mRNA and p90(MDM2) following UV exposure. We found that transcription of mdm2 was reduced in TCR-deficient cells. The uninducible mdm2 promoter, P1, was more sensitive to the inhibitory effects of UV irradiation than the P2 promoter. The decrease in transcription from the P1 promoter was sufficient to reduce the level of p90(MDM2) and correlated with a prolonged increase in p53. Thus, p53-independent transcription of mdm2 appears critical to p53's regulation.
Michalowski
J
J
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706, USA.
Seavey
S E
SE
Mendrysa
S M
SM
Perry
M E
ME
D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology / Q000528:radiation effects*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D016158:Genes, p53 / Q000528:radiation effects; D006801:Humans; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000528:radiation effects*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism / Q000528:radiation effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2