The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence
- Ozlem Aksoy1,2,3,6,
- Agustin Chicas1,3,6,
- Tianying Zeng4,
- Zhen Zhao1,3,
- Mila McCurrach3,
- Xiaowo Wang4 and
- Scott W. Lowe1,3,5,7
- 1Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
- 2Watson School of Biological Sciences,
- 3Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- 4MOE Key Laboratory of Bioinformatics, Bioinformatics Division, TNLIST, Department of Automation, Tsinghua University, Beijing 100084, China;
- 5Howard Hughes Medical Institute, New York, New York 10065, USA
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↵6 These authors contributed equally to this work.
Abstract
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.
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Footnotes
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↵7 Corresponding author
E-mail lowes{at}mskcc.org
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.196238.112.
- Received May 14, 2012.
- Accepted June 11, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press