The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

被引:103
作者
Aksoy, Ozlem [1 ,2 ,3 ]
Chicas, Agustin [1 ,2 ]
Zeng, Tianying [4 ]
Zhao, Zhen [1 ,2 ]
McCurrach, Mila [2 ]
Wang, Xiaowo [4 ]
Lowe, Scott W. [1 ,2 ,5 ]
机构
[1] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA
[2] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA
[3] Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA
[4] Tsinghua Univ, MOE Key Lab Bioinformat, Bioinformat Div, TNLIST,Dept Automat, Beijing 100084, Peoples R China
[5] Howard Hughes Med Inst, New York, NY 10065 USA
关键词
p53; target; mitosis; checkpoint; compensation; RB; E2F7; ONCOGENE-INDUCED SENESCENCE; DNA-BINDING DOMAINS; NF-KAPPA-B; TRANSCRIPTION-FACTOR; RETINOBLASTOMA GENE; TUMOR-SUPPRESSION; EMERGING ROLES; NETWORK; CANCER; RAS;
D O I
10.1101/gad.196238.112
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.
引用
收藏
页码:1546 / 1557
页数:12
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