Participation of p53 protein in the cellular response to DNA damage.
The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, gamma-irradiation or actinomycin D, causes a transient inhibition of replicative DNA synthesis via both G1 and G2 arrests. Levels of p53 protein in ML-1 cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the G1 arrest. In contrast, the S-phase arrest of ML-1 cells caused by exposure to the anti-metabolite, cytosine arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the G1 arrest and the induction of p53 protein after gamma-irradiation, thus suggesting that blocking the induction of p53 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike ML-1 cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the p53 gene do not exhibit a G1 arrest after gamma-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
M B
MB
Kastan
O
O
Onyekwere
D
D
Sidransky
B
B
Vogelstein
R W
RW
Craig
D001854:Bone Marrow Cells; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D003513:Cycloheximide; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D005091:Exons; D005434:Flow Cytometry; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D006801:Humans; D009154:Mutation / Q000235:genetics*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D002110:Caffeine; D003513:Cycloheximide