(from the application): Mammalian E2F is composed of a family of heterodimeric proteins encoded by six distinct genes and its important role in the control of cellular proliferation has now been demonstrated in mammals, in Drosophilia, and is thought to play a fundamental role in all other eukaryotes. Our recent findings have pointed to a role for the E2F3 gene locus as a particularly important regulator of the cell cycle by encoding two independent but overlapping transcription units that direct the synthesis of two distinct proteins, E2F3a and E2F3b. In contrast to E2F3a activity which is cell cycle regulated, peaking at every G1/S transition, the novel E2F3b protein is expressed in quiescent cells and specifically associates with Rb, representing the predominant E2F-Rb complex in non-proliferating cells. In view that the tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes, we view the E2F3b protein as having a potentially important role in regulating cell cycle entry/exit by its virtue of forming a transcriptional repressor with Rb. The proposed studies will aim to elucidate the role and mechanism of action of the E2F3 gene locus in the regulation of the cell cycle. We will take advantage of Cre-lox technologies to generate mice with conditional null alleles for each of the two E2F gene products to study their function in vivo. Moreover, this approach will allow us to execute sophisticated cell cycle studies in cells lacking multiple members of the E2F family. These studies will involve three specific aims: 1. To generate mice deficient for E2F3a, E2F3b, or both E2F3a and E2F3b. 2. To evaluate the role of the E2F3 gene locus in the control of cell proliferation and tumorigenesis in vivo. 3. To investigate the roles of E2F3a and E2F3b in the control of the cell cycle and cell proliferation in vitro. The long term goal of these studies is to molecularly dissect how the E2F transcriptional program contributes, in concert with other signaling pathways, towards the control of cell proliferation. The Rb/E2F pathway which is key in controlling cell cycle progression and cellular proliferation is almost always sabotaged during cancer development, and it is through the molecular understanding of these processes that we hope to contribute to the development of future cancer therapy.
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