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 elucidate the individual and combinatorial contributions made by these two highly related family members towards the overall understanding of E2F transcriptional activity.
The E2F family of transcription factors is believed to play a critical role in the control of cell cycle, apoptosis and differentiation. The identification of E2F7 and E2F8 as the final members of the E2F family, together with the generation of novel biochemical and genetic reagents, poise our group in a unique position to elucidate the individual and combinatorial contributions made by these two highly related family members towards the control of the cell cycle and apoptosis. These studies could help reveal how such mechanisms might contribute to the cancer phenotype.
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