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Context-specific Functions of CDK8

CDK8 的上下文特定功能

基本信息

批准号：
10549761
负责人：
Jun-yuan Ji
金额：
$ 33.9万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549761
关键词：
Abbreviations Binding Proteins Biochemical Biological Biology Cardiovascular Diseases Cell Cycle Cell Line Child Clinical Colorectal Cancer Complex Coupled Cyclin-Dependent Kinases DNA Binding Data Development Disease Drosophila genus Drosophila melanogaster E2F transcription factors EGF gene Epidermal Growth Factor Epidermal Growth Factor Receptor Eukaryota Factor Analysis Funding G1 Phase G1/S Transition Gene Expression Genes Genetic Genetic Screening Genetic Transcription Genome Stability Genomics Goals Homeostasis Human Immunoprecipitation Intake Length Link Malignant Neoplasms Mammals Mass Spectrum Analysis Mediator Modeling Mutate Nutrient Pathologic Pathway interactions Phase Transition Phenocopy Phenotype Phosphotransferases Polymerase Positioning Attribute Protein Analysis Proteins Proteomics RNA Polymerase II Receptor Signaling Regulation Reporting Repression Research Response Elements Retrotransposon Role Serum Response Factor Signal Pathway Sterols System Telomere Capping Testing Trans-Activators Transforming Growth Factor beta Up-Regulation Wing cofactor cyclin C design ecdysone receptor fly gene repression genetic analysis genomic locus human disease in vivo inhibitor lipid biosynthesis lipid metabolism melanoma model organism mutant novel public health relevance receptor restraint synergism telomere transcription factor transcriptome sequencing

项目摘要

Title: Context-specific functions of CDK8 Project Summary: The long-term goal of this project is to elucidate the function and regulation of the CDK8 module, a key component of the transcription cofactor Mediator complex, in the versatile model organism Drosophila melanogaster. The four subunits of the CDK8 module – CDK8, CycC, MED12, and MED13 – are either mutated or amplified in cardiovascular diseases and a number of human cancers, such as melanoma and colorectal cancers. Elucidating the function and regulation of the CDK8 module in different biological contexts is essential to understanding the pathological consequences of CDK8 module misregulation, which is important for the design of clinical strategies to treat these diseases. Studies in the previous funding cycle of this project have demonstrated that CDK8-CycC serves as a critical regulatory node linking nutrient intake to fat metabolism and developmental timing in Drosophila development. These studies have shown that CDK8-CycC is a direct inhibitor of SREBP (sterol response element binding protein)-dependent gene expression, and that CDK8-CycC positively regulates ecdysone receptor-activated gene expression. The overall objective of this project is to unravel the function and regulation of CDK8 in different developmental contexts. Studies in the previous funding cycle illustrate that Drosophila is an ideal and powerful experimental system to achieve this long-term goal. Two new aims are proposed in this funding cycle. Aim 1 will determine the role of CDK8 in regulating the expression of telomeric retrotransposons and telomere biology in Drosophila. Our RNA-seq analyses revealed a specific upregulation of telomeric retrotransposon expression and a significant increase in telomere length in cdk8 and cycC mutants. We have also discovered similar deregulation of telomeric retrotransposon expression and telomere length in med7 and Scalloped (Sd) mutants. The transcription factor Sd functions downstream of the conserved Hippo pathway. Thus we propose to examine the unexplored functions of the CDK8 module and Sd in regulating the expression of telomeric retrotransposons and telomere length in Drosophila. Aim 2 of the proposal will identify and validate upstream regulators and downstream effectors of CDK8 in Drosophila. We have established novel and robust wing phenotypes caused by specific alterations of CDK8 activities, allowing us to perform a dominant modifier genetic screen to identify factors interacting with CDK8 in vivo. We have identified 26 genomic loci whose haploinsufficiency modifies these CDK8-specific phenotypes; further genetic analysis led us to identify genetic interactions between CDK8 and the components of the epidermal growth factor receptor (EGFR) and Dpp/TGFβ signaling pathways, as well as several specific genes. In parallel, we have performed immunoprecipitation coupled to mass spectrometry (IP- MS) analyses to identify proteins that can interact with CDK8. Combination of these biochemical and genetic screens puts us in a unique position to systematically identify and validate upstream regulators and down- stream effectors of CDK8 in vivo, which will impact our understanding of the context-specific functions of CDK8.

题目：CDK8的上下文特异性功能