p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage.
Cells expressing the R273H mutant of p53, which lacks sequence specific DNA binding capacity, do not undergo cell cycle arrest in G1 following exposure to ionizing or UV radiation because of their inability to induce p21Waf1/Cip1, a cyclin-dependent kinase inhibitor and downstream mediator of p53-dependent DNA damage-induced growth arrest. Following UV-irradiation or treatment with an inhibitor of RNA pol II, we observed a rapid induction of the apoptotic process, as evidenced by DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase. Using mimosine, a p21Waf1/Cip1 inducer that bypasses the requirement for transcriptional transactivation by p53, we demonstrated that a G1 cell cycle arrest can prevent apoptosis following UV-irradiation or treatment with an RNA polymerase 11 inhibitor. Serum starvation, which also synchronized cells in G1 but did not induce p21Waf1/Cip1, did not protect cells from apoptosis. These results demonstrate that restoring a late G1 checkpoint by inducing p21Waf1/Cip1 expression can protect cells from DNA damage induced apoptosis. Our results suggest that p21Waf1/Cip1 can interrupt the apoptotic process at a point downstream from p53 accumulation but upstream from caspase-3 activation.
MRC Group in the Radiation Sciences, Faculté de médecine, Université de Sherbrooke, QC, Canada.
N
N
Bissonnette
D J
DJ
Hunting
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002277:Carcinoma; D053148:Caspase 3; D020169:Caspases; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase / Q000502:physiology*; D008898:Mimosine / Q000494:pharmacology; D009154:Mutation; D010507:Periodicity; D011065:Poly(ADP-ribose) Polymerases; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53; D014466:Ultraviolet Rays
D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D008898:Mimosine; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases