Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation.
The apoptotic response and the level of expression of p53 and of three genes transcriptionally activated by p53 (Mdm2, p21 and bax) were investigated in UV-sensitive cells from patients with xeroderma pigmentosum (XP) or Cockayne syndrome (CS). These disorders are due to different genetic defects affecting transcription-coupled repair (TCR) and/or global genome repair (GGR), the nucleotide excision repair subpathways which remove UV-induced lesions from the transcribed strand of active genes or from the rest of the genome, respectively. After 20 J/m2 UV light, normal and GGR-defective XP-C fibroblasts showed rapid increase in p53, late induction of Mdm2 and no evidence of apoptosis even 96 h after irradiation. In contrast, in XP-A (defective in GGR and TCR), CS-A and CS-B (defective only in TCR) fibroblasts, the p53 increase was not followed by Mdm2 induction and the persistence of high levels of p53, due to the lack of its degradation by Mdm2, was associated with the appearance of apoptosis. Besides indicating that the persistence of DNA damage in the transcribed strand of active genes leads to apoptosis, these findings provide the first evidence that the lack of activation of Mdm2 plays a key role in the cascade of events leading to apoptosis. Oncogene (2000).
Conforti
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Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milano, Italy.
Nardo
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D'Incalci
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Stefanini
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D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects*; D002478:Cells, Cultured; D004260:DNA Repair; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology / Q000528:radiation effects; D016158:Genes, p53; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000473:pathology* / Q000503:physiopathology; D051028:bcl-2-Associated X Protein; D018631:ras Proteins / Q000502:physiology
C494826:BAX protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D018631:ras Proteins