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成分的去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。在用果蝇进行的研究中，我们发现Cyclin D/CDK4复合体除了被广泛认为是细胞周期进程的促进剂外，还调节细胞质量(生长)的增加速度。CyCD/CDK4通过未知的靶点完成这一过程，这与那些研究得很好的PRB/E2F途径不同。我们正在使用果蝇遗传学来识别和表征这些新的生长调节靶点，我们相信这可能对于理解CyCD/CDK4在正常和肿瘤发育过程中的功能很重要。该项目的具体目标包括：1)利用已证实的全基因组筛选主要抑制异位CyCD/CDK4引起的眼睛过度生长的突变来鉴定和鉴定CyCD/CDK4的生长调控靶点；2)通过基因表达谱鉴定CyCD/CDK4靶点；3)建立果蝇CYCD/CDK4激酶实验来表征可能的靶点；4)表征HPH/HIF-1/VHL和JAK/STAT通路作为CYCD/CDK4驱动的生长的中介；以及5)测试以确定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来影响细胞生长。该项目旨在阐明CyCD/CDK4如何改变细胞生理以促进生长，并应有助于解释细胞生长和细胞分裂是如何耦合的分子范式。它还可以在人类中识别新的Cyclin D和INK4靶点，从而有助于揭示我们自己的细胞在正常和肿瘤发育过程中是如何控制生长的。其中一些已识别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.