Growth-regulatory targets of Drosophila Cyclin D/Cdk4

描述（由申请人提供）：Ink4/Cyclin D1/视网膜母细胞瘤通路中至少一个组分的解除调控是大多数人类癌症的共同特征，但这些基因促进肿瘤发生的机制尚不清楚。在对果蝇的研究中，我们发现Cyclin D/Cdk4复合物，除了作为细胞周期进程的促进者而被广泛认可的功能外，还调节细胞质量（生长）的增加速率。CycD/Cdk4通过未知靶点实现这一点，不同于那些已被充分研究的pRb/E2F途径。我们正在使用果蝇遗传学来识别和表征这些新的生长调控靶点，我们相信这可能对理解正常和肿瘤发育过程中CycD/Cdk4的功能很重要。该项目的具体目标包括：1)利用成熟的全基因组筛选，鉴定和表征CycD/Cdk4的生长调控靶点，这些突变主要抑制由异位CycD/Cdk4引起的眼睛过度生长；2)利用基因表达谱鉴定CycD/Cdk4靶点；3)开发果蝇CycD/Cdk4激酶检测方法，用于鉴定推测的靶点；4)表征Hph/Hif-1/VHL和JAK/STAT通路作为CycD/ cdk4驱动生长的介质；5)检测CycD/Cdk4是否通过调节营养输入、蛋白质合成、蛋白质降解或线粒体功能影响细胞生长。该项目旨在阐明CycD/Cdk4如何改变细胞生理以促进生长，并有助于解释细胞生长和细胞分裂如何耦合的分子范式。它还可以鉴定人类体内新的Cyclin D和Ink4靶点，从而有助于揭示在正常和肿瘤发育过程中我们自身细胞的生长是如何被控制的。其中一些已确定的基因可能成为癌症诊断或抗癌化疗的有用靶点。

DESCRIPTION (provided by applicant): Deregulation of at least one component of the Ink4/Cyclin D1/retinoblastoma pathway is a common feature of most of human cancers, but the mechanism by which these genes contribute to tumorigenesis is poorly understood. In studies using Drosophila we discovered that Cyclin D/Cdk4 complexes, in addition to their widely appreciated function as promoters of cell cycle progression, also regulate rates of increase in cell mass (growth). CycD/Cdk4 does this via unknown targets, distinct from those in the well-studied pRb/E2F pathway. We are using Drosophila genetics to identify and characterize these novel growth-regulatory targets, which we believe may be important for understanding CycD/Cdk4 function during normal and neoplastic development. Specific aims of this project comprise: 1) Identification and characterization of growth regulatory targets of CycD/Cdk4 using proven, genome-wide screens for mutations that dominantly suppress overgrowth of the eye caused by ectopic CycD/Cdk4; 2) Identification of CycD/Cdk4 targets by gene expression profiling; 3) development of a Drosophila CycD/Cdk4 kinase assay for characterizing putative targets; 4) Characterizing the Hph/Hif-1/VHL and JAK/STAT pathways as mediators of CycD/Cdk4-driven growth; and 5) Tests to determine whether CycD/Cdk4 effects cellular growth by modulating nutrient import, protein synthesis, protein degradation, or mitochondrial function. This project aims to elucidate how CycD/Cdk4 alters cell physiology to promote growth, and should contribute to molecular paradigms explaining how cell growth and cell division are coupled. It should also allow identification of novel Cyclin D and Ink4 targets in humans, and thus help to reveal how growth of our own cells is controlled during normal and neoplastic development. Some of the identified genes could be useful targets for cancer diagnosis or anti-cancer chemotherapeutics.