P53 plays a protective role against UV- and cisplatin-induced apoptosis in transcription-coupled repair proficient fibroblasts.
We previously reported that transcription-coupled repair (TCR)-deficient human fibroblasts are extremely sensitive to UV-induced apoptosis and this sensitivity correlated with the induction of the p53 tumour suppressor. However, we have also found that p53 can be protective against UV-induced apoptosis. Thus, prior to this study, it was not clear whether the induction of p53 in TCR-deficient fibroblasts contributed to their death. To address this issue, we have expressed human papillomavirus E6 (HPV-E6) in primary fibroblasts derived from patients affected with xeroderma pigmentosum (complementation groups A, B and C) and Cockayne syndrome (complementation group B). We found that TCR-deficient (XP-A, XP-B and CS-B) fibroblasts were more sensitive than TCR-proficient cells (XP-C and normal) to both UV light and cisplatin treatment and this increase in sensitivity was not p53 dependent. Importantly, HPV-E6 expression increased the sensitivity of TCR-proficient normal and XP-C fibroblasts to UV- and cisplatin-induced apoptosis. This increase in sensitivity correlated with a decrease in the capacity of HPV-E6 expressing cells to recover mRNA synthesis following UV-irradiation. Therefore, we propose that p53 protects against UV- and cisplatin-induced apoptosis in a TCR-dependent manner and that p53 does not contribute strongly to the induction of apoptosis in TCR-deficient fibroblasts.
McKay
B C
BC
Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, 503 Smyth Road, Ottawa, Ontario K1H 1C4, Canada.
Becerril
C
C
Ljungman
M
M
D017209:Apoptosis; D002945:Cisplatin / Q000494:pharmacology*; D003057:Cockayne Syndrome / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D012097:Repressor Proteins; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000378:metabolism / Q000473:pathology
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin