Wild-type p53 is a cell cycle checkpoint determinant following irradiation.
Cell cycle checkpoints appear to contribute to an increase in cell survival and a decrease in abnormal heritable genetic changes following exposure to DNA damaging agents. Though several radiation-sensitive yeast mutants have been identified, little is known about the genes that control these responses in mammalian cells. Recent studies from our laboratory have demonstrated a close correlation between expression of wild-type p53 genes in human hematopoietic cells and their ability to arrest in G1 phase after certain types of DNA damage. In the present study, this correlation was first generalized to nonhematopoietic mammalian cells as well. A cause and effect relationship between expression of wild-type p53 and the G1 arrest that occurs after gamma irradiation was then established by demonstrating (i) acquisition of the G1 arrest after gamma irradiation following transfection of wild-type p53 genes into cells lacking endogenous p53 genes and (ii) loss of the G1 arrest after irradiation following transfection of mutant p53 genes into cells with wild-type endogenous p53 genes. A defined role for p53 (the most commonly mutated gene in human cancers) in a physiologic pathway has, to our knowledge, not been reported previously. Furthermore, these experiments illustrate one way in which a mutant p53 gene product can function in a "dominant negative" manner. Participation of p53 in this pathway suggests a mechanism for the contribution of abnormalities in p53 to tumorigenesis and genetic instability and provides a useful model for studies of the molecular mechanisms of p53 involvement in controlling the cell cycle.
Kuerbitz
S J
SJ
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Plunkett
B S
BS
Walsh
W V
WV
Kastan
M B
MB
D002453:Cell Cycle / Q000528:radiation effects*; D002460:Cell Line; D003110:Colonic Neoplasms; D004249:DNA Damage; D004261:DNA Replication / Q000528:radiation effects*; D005720:Gamma Rays; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D012867:Skin; D014162:Transfection