The tumor suppressor p53 can both stimulate and inhibit ultraviolet light-induced apoptosis.
We have previously shown that the tumor suppressor p53 can play a protective role against UV-induced apoptosis in human fibroblasts. In the present study, we investigated whether the protective function of p53 expression is established before or after UV irradiation. Using a stable human cell line expressing a murine temperature-sensitive p53 in which p53 function could be tightly and reversibly regulated, we found that functional p53 stimulated the induction of apoptosis when expressed for as little as 4-12 h after UV irradiation and that this induction was not dependent on de novo protein synthesis. In contrast, expression of p53 for 12 h or more before UV irradiation reduced the extent of apoptosis even when functional p53 expression was maintained after irradiation. The protection conferred by p53 required ongoing protein synthesis and correlated with enhanced recovery of mRNA synthesis. Together, these results suggest that p53 induces distinct proapoptotic and antiapoptotic signals and that these opposing activities can be separated both temporally and by their requirement for de novo protein synthesis. These findings may have important implications for the refinement of gene therapy approaches combining p53 with pharmacological agents that target transcription or translation.
Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0936, USA.
B C
BC
McKay
F
F
Chen
C R
CR
Perumalswami
F
F
Zhang
M
M
Ljungman
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D002453:Cell Cycle; D003513:Cycloheximide / Q000494:pharmacology; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D008954:Models, Biological; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays
D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide