WILD-TYPE P53 IS A CELL-CYCLE CHECKPOINT DETERMINANT FOLLOWING IRRADIATION
WILD-TYPE P53 IS A CELL-CYCLE CHECKPOINT DETERMINANT FOLLOWING IRRADIATION
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DOI：
10.1073/pnas.89.16.7491
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发表时间：
1992-08-15
影响因子：
11.1
通讯作者：
KASTAN, MB
中科院分区：
文献类型：
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作者：
KUERBITZ, SJ;PLUNKETT, BS;KASTAN, MB
细胞周期检查点似乎有助于增加细胞存活率和减少暴露于DNA损伤剂后的异常遗传性遗传变化。虽然已经鉴定了几种辐射敏感的酵母突变体，但对哺乳动物细胞中控制这些反应的基因知之甚少。我们实验室最近的研究表明，在人类造血细胞中野生型p53基因的表达与其在某些类型的DNA损伤后在G1期停滞的能力之间存在密切的相关性。在本研究中，这种相关性首次推广到非造血哺乳动物细胞。然后，通过证明（i）在将野生型p53基因转染到缺乏内源性p53基因的细胞中之后，在γ-照射之后获得G1停滞，和（ii）在将突变型p53基因转染到具有野生型p53基因的细胞中之后，在γ-照射之后失去G1停滞，建立了野生型p53的表达和γ-照射之后发生的G1停滞之间的因果关系。型内源性p53基因。据我们所知，p53（人类癌症中最常见的突变基因）在生理途径中的明确作用以前尚未报道。此外，这些实验说明了突变型p53基因产物可以以“显性负性”方式发挥功能的一种方式。p53参与这一通路表明了p53异常对肿瘤发生和遗传不稳定性的贡献机制，并为研究p53参与控制细胞周期的分子机制提供了有用的模型。
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.