细胞周期检查点
激酶
细胞生物学
细胞周期
RNA干扰
抑制器
生物
细胞凋亡
程序性细胞死亡
细胞命运测定
癌症研究
细胞
支票1
癌细胞
基因
癌症
核糖核酸
转录因子
遗传学
作者
Kelly D. Sullivan,Nuria Padilla-Just,Ryan E. Henry,Christopher C. Porter,Jihye Kim,John J. Tentler,S. Gail Eckhardt,Aik Choon Tan,James DeGregori,Joaquín M. Espinosa
摘要
The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small-molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a genome-wide short hairpin RNA screen for genes that are lethal in combination with p53 activation by Nutlin-3, which showed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors also enable Nutlin-3 to kill tumor spheroids. These results identify new pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies.
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