E2F3 GENE LOCUS IN THE CONTROL OF CELL PROLIFERATION

描述(来自应用程序)：哺乳动物E2F由一个家族组成 六个不同基因编码的异源二聚体蛋白及其在细胞周期中的重要作用 现在已经在哺乳动物身上证明了对细胞增殖的控制， 果蝇，被认为在所有其他真核生物中起着基础性的作用。 我们最近的发现表明，E2F3基因座在 尤其重要的是通过编码两个独立的细胞周期调节器 但重叠的转录单位指导着两个不同的 蛋白质，E2F3a和E2F3b。与E2F3a活性相反，E2F3a活性是细胞周期 受调控，在每一次G1/S转变时达到峰值，新的E2F3b蛋白是 在静止细胞中表达，并与Rb特异性结合，代表 在非增殖细胞中主要是E2F-Rb复合体。有鉴于此 Rb的抑癌功能与其抑制肿瘤的能力密切相关 我们认为，与E2F相互作用并抑制E2F靶基因的转录 E2F3b蛋白在细胞调节中的潜在重要作用 通过与Rb形成转录抑制因子来循环进入/退出。 拟议的研究将旨在阐明作用的作用和机制 E2F3基因在细胞周期调控中的作用。我们会利用这个优势 Cre-lox技术为每个产生条件空等位基因的小鼠 对两个E2F基因产物进行比较，研究它们在体内的功能。此外，这一点 方法将允许我们在细胞中执行复杂的细胞周期研究 缺乏E2F家族的多个成员。这些研究将涉及三项 具体目标： 1.产生E2F3a、E2F3b或E2F3a和E2F3b缺乏症小鼠。 2.探讨E2F3基因座在细胞调控中的作用 体内的增殖和成瘤。 3.探讨E2F3a和E2F3b在细胞周期调控中的作用 和细胞的体外增殖。 这些研究的长期目标是从分子上剖析E2F是如何 转录程序与其他信号通路协同作用， 朝着控制细胞增殖的方向发展。Rb/E2F途径是关键 控制细胞周期进程和细胞增殖几乎总是 在癌症发展过程中受到破坏，它是通过分子 了解这些进程，我们希望为发展做出贡献 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.