E2F3 GENE LOCUS IN THE CONTROL OF CELL PROLIFERATION

描述（来自申请）：哺乳动物E2 F由以下家族组成： 由六个不同基因编码的异二聚体蛋白及其在 细胞增殖的控制现在已经在哺乳动物中得到证实， 果蝇，并被认为在所有其他真核生物中发挥着重要作用。 我们最近的研究结果指出E2 F3基因位点作为一个重要的基因位点， 一种特别重要的细胞周期调节因子，编码两个独立的 但是重叠的转录单位指导两种不同的 蛋白质，E2 F3 a和E2 F3 b。与E2 F3 a活性相反， 调节，在每个G1/S转换达到峰值，新的E2 F3 b蛋白是 在静止期细胞中表达，并与Rb特异性结合，代表 非增殖细胞中主要的E2 F-Rb复合物。鉴于 Rb的肿瘤抑制功能与其抑制肿瘤生长的能力密切相关。 与E2 F相互作用并抑制E2 F靶基因的转录，我们认为 E2 F3 b蛋白在调节细胞中具有潜在重要作用 通过与Rb形成转录阻遏物的优点进入/退出循环。 拟议的研究旨在阐明 E2 F3基因位点在细胞周期调控中的作用。我们将利用 Cre-lox技术，以产生具有条件无效等位基因的小鼠， 的两个E2 F基因产物，以研究其在体内的功能。而且这 这种方法将使我们能够在细胞中进行复杂的细胞周期研究， 缺乏E2 F家族的多个成员。这些研究将涉及三个 具体目标： 1.产生E2 F3 a、E2 F3 b或E2 F3 a和E2 F3 b缺陷的小鼠。 2.探讨E2 F3基因位点在细胞凋亡调控中的作用 增殖和体内肿瘤发生。 3.探讨E2 F3 a和E2 F3 b在细胞周期调控中的作用 和体外细胞增殖。 这些研究的长期目标是从分子水平上剖析E2 F是如何在 转录程序，与其他信号通路一起， 控制细胞增殖。Rb/E2 F通路是 控制细胞周期进程和细胞增殖几乎总是 在癌症发展过程中被破坏，它是通过分子 了解这些过程，我们希望有助于发展 未来的癌症治疗。

DESCRIPTION (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.