The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence.
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.
Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Ozlem
O
Aksoy
Agustin
A
Chicas
Tianying
T
Zeng
Zhen
Z
Zhao
Mila
M
McCurrach
Xiaowo
X
Wang
Scott W
SW
Lowe
D000818:Animals; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D050702:E2F7 Transcription Factor; C481054:E2F7 protein, human; C479901:E2f7 protein, mouse; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53