The E2F family of transcription factors are encoded by eight distinct genes that based on structure-function studies and amino acid sequence analysis, fall into two main subclasses, activator E2Fs (E2F1-3) and repressor E2Fs composed of canonical repressors (E2F4-6) and atypical repressors (E2F7-8). Unlike other E2F family members, E2F7 and E2F8 bind DNA independent of dimerization with DP1/DP2 proteins and lack amino acid sequences typically used to interact with Rb-related proteins, and thus these atypical E2Fs may function outside the canonical CDK-Rb-E2F pathway. With the recent development of key genetic tools to conditionally disrupt or express E2f7 and E2f8 in mice, knocking mice that conditionally express endogenous wild type and mutant forms of E2F8 protein and knockin mice containing altered promoters of two key E2F-responsive target genes (Cdc6 and Cyclin A2) we expect to make significant strides towards a mechanistic understanding of how this important arm of the E2F family contribute to the control of transcription, cell cycle, and tumor suppression in vivo. Key preliminary data shows that E2F8 plays a critical role in endocycles and tumor suppression in the mouse liver and that its activity appears to be mediated by physical interactions with E2F7 and associated macro-molecular complexes to regulate gene expression outside the influence of the Cdk-Rb pathway. The overarching hypothesis of this proposal is that E2F8 functions as a transcriptional repressor to control cell cycles, genome ploidy levels and acts as a tumor suppressor in HCC.
Three specific aims utilizing genetic, biochemical, and global profiling approaches will directly test this hypothesis. The long-term goal of these studies is to understand how the "atypical (E2F8) arm" contributes to the overall E2F transcriptional program in controlling cell cycles and tumor suppression.

Public Health Relevance

E2F8 is one member of a large family of genes that are important to control gene expression. We have preliminary evidence showing that E2F8 is a key regulator of cell cycles and is able to block tumorigenesis in the liver, and we now plan to study how E2F8 carries out these critical roles in animals. The long-term goal of these studies is to understand how the atypical (E2F8) arm contributes to the overall E2F program in controlling gene expression, cell cycles and tumor suppression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Johnson, Ronald L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Kent, Lindsey N; Rakijas, Jessica B; Pandit, Shusil K et al. (2016) E2f8 mediates tumor suppression in postnatal liver development. J Clin Invest 126:2955-69
Trikha, P; Sharma, N; Pena, C et al. (2016) E2f3 in tumor macrophages promotes lung metastasis. Oncogene 35:3636-46
Tang, Xing; Liu, Huayang; Srivastava, Arunima et al. (2016) Transcriptome regulation and chromatin occupancy by E2F3 and MYC in mice. Sci Data 3:160008
Wu, L; de Bruin, A; Wang, H et al. (2015) Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis. Oncogene 34:119-28
Liu, Huayang; Tang, Xing; Srivastava, Arunima et al. (2015) Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles. Nat Cell Biol 17:1036-48
Caserta, Enrico; Egriboz, Onur; Wang, Hui et al. (2015) Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. Genes Dev 29:1707-20
Zeng, X; Shaikh, F Y; Harrison, M K et al. (2010) The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2. Oncogene 29:5103-12
Trimboli, Anthony J; Cantemir-Stone, Carmen Z; Li, Fu et al. (2009) Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461:1084-91
Lammens, Tim; Li, Jing; Leone, Gustavo et al. (2009) Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol 19:111-8
Chen, Danian; Pacal, Marek; Wenzel, Pamela et al. (2009) Division and apoptosis of E2f-deficient retinal progenitors. Nature 462:925-9

Showing the most recent 10 out of 13 publications