The E2F family of transcription factors is believed to play a critical role in the control of cellular proliferation. These factors are encoded by distinct genes and have both tumor suppressor and oncogenic functions (1-2). Our laboratory identified E2F7 and E2F8 as the final two members of this transcription factor family (5, 6). The preliminary data presented in this proposal highlight several unique features of these two E2Fs that place them in a subclass of their own. These salient features include their ability to form homodimers and heterodimers, to associate with a large cadre of transcriptional co-repressors, to silence gene expression, and to block cellular proliferation. While they lack a typical Rb-binding domain, E2F7 can specifically interact with Rb related proteins and can thus recruit E2F8 to Rb-containing complexes. As a result, the E2F7/8 arm of the E2F network remains under the control of the cycling dependent kinase (CDK) signaling pathway. The fact that E2F7 and E2F8 have an identical pattern of cell cycle dependent and tissue- specific expression, together with their ability to homo- and hetero-dimerize, raises the possibility that they may have both unique and shared functions in the animal. A multi-faceted effort in the laboratory has yielded key technical developments, including an affinity purification strategy to purify E2F7/8-associated proteins, promoter-array technologies to identify target genes, and gene targeting approaches to disrupt E2F7 and E2F8 in mice. These advances place our research group in a strong position to make significant advances towards a mechanistic understanding of how this important arm of the E2F family of factors controls the cell cycle and cell proliferation. The overarching hypothesis of this proposal is that E2F7 and E2F8 function as transcriptional repressors to negatively control cellular proliferation.
Three specific aims utilizing biochemical, biophysical, global gene array, and genetic approaches will directly test this hypothesis:
Specific Aim 1. To identify and characterize E2F7- and E2F8-associated macromolecular protein complexes.
Specific Aim 2. To identify E2F7 and E2F8 transcriptional targets.
Specific Aim 3. To determine the mechanism of E2F7 and E2F8 action in the control of transcription. This work will elucida the individual and combinatorial contributions made by these two highly related family members towards the overall understanding of E2F transcriptional activity. Project Description Page 6
|Okano-Uchida, Takayuki; Kent, Lindsey N; Ouseph, Madhu M et al. (2018) Endoreduplication of the mouse genome in the absence of ORC1. Genes Dev 32:978-990|
|Liu, Huayang; Dowdle, James A; Khurshid, Safiya et al. (2017) Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation. Dev Cell 41:392-407.e6|
|Tang, Xing; Srivastava, Arunima; Liu, Huayang et al. (2017) annoPeak: a web application to annotate and visualize peaks from ChIP-seq/ChIP-exo-seq. Bioinformatics 33:1570-1571|
|Kent, Lindsey N; Bae, Sooin; Tsai, Shih-Yin et al. (2017) Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest 127:830-842|
|Thurlings, I; Martínez-López, L M; Westendorp, B et al. (2017) Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer. Oncogene 36:829-839|
|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|
|Jones, Robert A; Robinson, Tyler J; Liu, Jeff C et al. (2016) RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J Clin Invest 126:3739-3757|
|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|
|Julian, L M; Liu, Y; Pakenham, C A et al. (2016) Tissue-specific targeting of cell fate regulatory genes by E2f factors. Cell Death Differ 23:565-75|
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