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Pattern Formation in the Drosophila Eye Disc

果蝇眼盘的图案形成

基本信息

批准号：
9222013
负责人：
Jessica E Treisman
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222013
关键词：
Affect Age related macular degeneration Aging Binding Biochemical Biological Models Cancer Etiology Cell Nucleus Cells Complex Cullin Proteins Defect Development Diagnosis Disease Drosophila eye Drosophila genus Epidermal Growth Factor Receptor Event Excision Eye Eye Development Failure Family Dasypodidae Gene Expression Gene Targeting Genes Genetic Genetic Screening Genetic Transcription Genome Health Hereditary Disease Homologous Gene Human Invertebrates Investigation Lead Ligands Malignant Neoplasms Maps Mediating Mediator of activation protein Methods Modification Molecular Mutation Neurodegenerative Disorders Organ Organism Pathway interactions Pattern Formation Phenotype Phosphorylation Photoreceptors Physiological Play Post-Translational Protein Processing Process Proteins Proteomics RNA Interference Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Retinal Role Signal Pathway Signal Transduction Site System Testing Tissues Transcription Coactivator Transgenic Organisms Ubiquitin Ubiquitin Like Proteins Ubiquitination WNT Signaling Pathway base cancer therapy experimental study gene cloning genetic approach insight knock-down multicatalytic endopeptidase complex mutant mutation screening novel prevent protein degradation public health relevance retinal progenitor cell scaffold tool transcription factor ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The Wnt and receptor tyrosine kinase signaling pathways play important roles in regulating eye development in both vertebrate and invertebrate systems. Signal transduction through these pathways depends on changes in protein stability, and protein degradation is also an important defense against aging and disease. Proteins are marked for degradation by ubiquitination, and ubiquitin ligases themselves are regulated by neddylation, a modification that increases their activity but also promotes their turnover. This proposal will investigate the functions and regulation of ubiquitin ligase complexes and protein stability in Wnt and Epidermal Growth Factor Receptor (EGFR) signaling and in other aspects of Drosophila eye development. A genetic screen for genes required for normal photoreceptor differentiation found that mutations in CSN1b, which encodes a subunit of the COP9 signalosome, result in reduced Wnt signaling and increased EGFR signaling. The best-known function of COP9 is to deneddylate Cullins, the scaffolding subunits of ubiquitin ligase complexes; however, CSN1b phenotypes cannot be explained by loss of Cullin function. The first aim is to test whether the effects of CSN1b are due to failure of deneddylation by the COP9 signalosome, and to understand how CSN1b alters signaling through the Wnt and EGFR pathways. Genetics and proteomics will be used to determine the components of each pathway that are affected, and test whether they are substrates for ubiquitination, neddylation, or other activities of COP9. The second aim is to understand how another gene identified in the same screen, disarmed (dsm), regulates Wnt signaling by preventing �-catenin accumulation but promoting its transcriptional activity. As dsm has been mapped to a small region of the genome, it should be possible to rapidly clone the gene, pinpoint its sites of action in the Wnt pathway, and investigate its mechanism of action. The results will lead to insights into how the stability o �-catenin can be uncoupled from its function as a transcriptional coactivator, a question relevant to anti- cancer therapies. The final aim is to search for novel functions and substrates for ubiquitin ligase complexes in eye development. A transgenic RNAi strategy will be used to screen the substrate-binding subunits of Cullin-based ubiquitin ligase complexes for functions in eye development. Substrates for conserved subunits with interesting knockdown phenotypes will be identified through a combination of phenotypic and biochemical analysis. The screen will reveal the extent to which protein stability is regulated during eye development, and will contribute to our understanding of the roles and mechanisms of protein turnover in development and disease.

描述(申请人提供)：Wnt和受体酪氨酸激酶信号通路在调节脊椎动物和无脊椎动物系统的眼睛发育方面发挥着重要作用。通过这些途径的信号转导依赖于蛋白质稳定性的变化，而蛋白质降解也是抵御衰老和疾病的重要防御措施。蛋白质被泛素化标记为降解，泛素连接酶本身受核苷酸修饰的调节，这种修饰增加了它们的活性，但也促进了它们的周转。这项建议将研究泛素连接酶复合体的功能和调节，以及在Wnt和表皮生长因子受体(EGFR)信号转导以及果蝇眼睛发育的其他方面的蛋白质稳定性。对正常光感受器分化所需基因的遗传筛选发现，编码COP9信号体一个亚单位的CSN1b突变导致Wnt信号减少和EGFR信号增加。COP9最著名的功能是使泛素连接酶复合体的支架亚基Cullins脱染；然而，CSN1b的表型不能用Cullin功能的丧失来解释。第一个目的是测试CSN1b的作用是否由于COP9信号小体去动力的失败，并了解CSN1b如何通过Wnt和EGFR途径改变信号。遗传学和蛋白质组学将被用来确定每个受影响的途径的成分，并测试它们是否是泛素化、核苷化或COP9其他活性的底物。第二个目的是了解在同一筛选中发现的另一个基因，disarm(Dsm)是如何通过阻止�-catenin的积累而促进其转录活性来调节Wnt信号的。由于DSM已被定位到基因组的一个小区域，因此应该有可能快速克隆该基因，确定其在Wnt途径中的作用部位，并研究其作用机制。这一结果将引导人们深入了解�-连环蛋白的稳定性如何与其作为转录辅助激活因子的功能分离，这是一个与抗癌治疗相关的问题。最终目的是寻找泛素连接酶复合体在眼睛发育中的新功能和底物。将使用转基因RNAi策略来筛选基于cullin的泛素连接酶复合体的底物结合亚基，以了解其在眼睛发育中的功能。具有有趣的击倒表型的保守亚基的底物将通过表型和生化分析相结合来鉴定。该屏幕将揭示在眼睛发育过程中蛋白质稳定性受到调节的程度，并将有助于我们理解蛋白质周转在发育和疾病中的作用和机制。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Drosophila Epidermal Growth Factor Receptor does not act in the nucleus.

果蝇表皮生长因子受体不在细胞核中起作用。

DOI：
10.1242/jcs.220251
发表时间：
2018
期刊：
Journal of cell science
影响因子：
4
作者：
Courgeon,Maximilien;He,DanQing;Liu,HuiHua;Legent,Kevin;Treisman,JessicaE
通讯作者：
Treisman,JessicaE

Coming to our senses.

DOI：
10.1002/bies.20083
发表时间：
2004-08
期刊：
BioEssays : news and reviews in molecular, cellular and developmental biology
影响因子：
0
作者：
J. Treisman
通讯作者：
J. Treisman

Retinal differentiation in Drosophila.