UV but not gamma irradiation accelerates p53-induced apoptosis of teratocarcinoma cells by repressing MDM2 transcription.
Induction of p53 by DNA damage results in apoptosis of teratocarcinoma cells, whereas MDM2, encoded by a p53-responsive gene, can reverse this phenotype by inhibiting p53 function. Here we report that UV (10 or 20 J/m2), but not gamma irradiation (7 or 10 Gy), caused a massive apoptosis of human teratoma Tera-2 or murine testicular carcinoma F9 cells, both of which contain wild-type p53, but not murine p53 null testicular carcinoma EB-16 cells. Most Tera-2 or F9 cells died overnight after UV but not gamma irradiation. Correlated with this phenotype was a dramatic and continuing accumulation of p53 proteins after UV but not gamma irradiation. This was attributable to UV-responsive repression of MDM2 expression, because both its protein and RNA were not detectable after UV irradiation. This UV-induced repression appeared to be specific to MDM2, because expression of other genes, such as p21, p53, or glyceraldehyde-3-phosphate dehydrogenase, was not reduced. Also, RNase protection analysis showed that a DNA region, excluding the p53 binding site, in the MDM2 promoter mediated transcriptional repression in response to UV. Thus, these results suggest that UV but not gamma irradiation can induce p53 by suppressing MDM2 expression in a p53-independent fashion and subsequently, massive cell death.
Zeng
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Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland 97201, USA.
Keller
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Wu
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Lu
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D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D020218:Response Elements / Q000528:radiation effects; D018243:Teratocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000528:radiation effects*; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays
D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2