Mip/LIN9 and Cell Proliferation

描述（由申请人提供）：细胞周期的G1期是调节细胞增殖的细胞外信号的靶点。有丝分裂刺激通过周期蛋白依赖激酶（CDKs）的有序激活来负责细胞周期进程，CDKs可灭活视网膜母细胞瘤或口袋蛋白家族成员pRB， p107和p130。了解细胞周期G1期的调控是至关重要的，因为其调控的改变可能导致计划外的DNA合成和肿瘤形成。口袋蛋白与E2F家族成员形成复合物，以调节一组特定基因的转录，这些基因被称为E2F调节基因，这是进入s期所必需的。CDK4、6和CDK2负责抑制pRB/E2F1-3和p107、p130/E2F4,5对细胞周期进程所需基因的抑制活性失活。这些抑制因子复合物含有其他有助于G0/G1调节的蛋白质。我们最近证明了一种在所有真核生物中具有同源物的新蛋白Mip/LIN-9参与细胞周期进程的调节。在本应用中，我们将验证Mip/LIN-9与口袋蛋白一样作用于CDK4下游的假设。我们认为G1激酶的活性是Mip/LIN-9从p107，p130/E2F4抑制因子复合体中释放的原因，并且这一步骤对于Mip/LIN-9与B-Myb在s期的结合至关重要，这两个蛋白都是G2/M基因的转录激活因子。我们还将阐明Mip/LIN-9是否对G0中抑制因子复合物的活性是必需的。最后，我们将建立一个完全缺失Mip/LIN-9基因的新动物模型，以确定其在其他细胞功能和发育中的作用。

DESCRIPTION (provided by applicant): The G1 phase of the cell cycle is the target of extracellular signals that regulate cell proliferation. Mitogenic stimuli are responsible for cell cycle progression via the orderly activation of cyclin-dependent kinases (CDKs) that inactivate members of the retinoblastoma or pocket protein family, pRB, p107 and p130. The understanding of the regulation of the G1 phase of the cell cycle is critical since alterations of its regulation could lead to unscheduled DNA synthesis and tumor formation. The pocket proteins form complexes with the E2F family members to regulate transcription of a specific set of genes, termed E2F-regulated genes, which are required for the passage into S-phase. CDK4,6 and CDK2 are responsible for the inactivation of the repressor activity that pRB/E2F1-3 and p107,p130/E2F4,5 exert on genes required for cell cycle progression. These repressor complexes contain other proteins that contribute to G0/G1 regulation. We recently demonstrated that a novel protein with homologs in all eukaryotes, Mip/LIN-9, participates in the regulation of cell cycle progression. In this application, we will test the hypothesis that Mip/LIN-9, like the pocket proteins, acts downstream of CDK4. We propose that the activity of this G1 kinase is responsible for the release of Mip/LIN-9 from the p107,p130/E2F4 repressor complex and that this step is critical for the association of Mip/LIN-9 with B-Myb is S-phase where both proteins function as transcriptional activators of the G2/M genes. We will also elucidate if Mip/LIN-9 is required for the activity of the repressor complex in G0. Finally, we will produce a new animal model with a complete deletion of the Mip/LIN-9 gene to determine its role in other cellular functions as well as in development. PUBLIC HEALTH RELEVANCE: The goal of this project is to characterize a protein termed Mip/LIN-9, which is responsible for the regulation of cell division and proliferation. This goal is relevant for the growth of all cell types but it is particularly relevant for cancer cells. The goals proposed in this project could produce importance advancement in understanding and treatment of different types of cancer.