WILD-TYPE P53 IS A CELL-CYCLE CHECKPOINT DETERMINANT FOLLOWING IRRADIATION

被引:1956
作者
KUERBITZ, SJ [1 ]
PLUNKETT, BS [1 ]
WALSH, WV [1 ]
KASTAN, MB [1 ]
机构
[1] JOHNS HOPKINS UNIV,SCH MED,DEPT ONCOL,BALTIMORE,MD 21205
关键词
GAMMA-IRRADIATION; DNA DAMAGE; DNA REPLICATION; CARCINOGENESIS;
D O I
10.1073/pnas.89.16.7491
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:7491 / 7495
页数:5
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