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Project 3: Defining and targeting mechanisms of E2F transcription factor regulation

项目3：E2F转录因子调控的定义和靶向机制

基本信息

批准号：
10597169
负责人：
Seth Michael Rubin
金额：
$ 23.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-25 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597169
关键词：
Acetylation Adaptor Signaling Protein Address Affinity Architecture Binding Biochemical Biochemistry Cancer Control Cancer Model Cell Cycle Cell Cycle Inhibition Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell division Cells Cellular Assay Cellular biology Chemicals Chromatin Collaborations Complex Consensus Cullin Proteins Cyclin-Dependent Kinases Cyclins DNA DNA biosynthesis Data Defect Dependence E2F transcription factors Enzymes Event G1/S Transition Gene Activation Gene Expression Genes Genetic Genetic Transcription Genomic approach Goals Growth Hydrophobicity Interphase Cell Knowledge Malignant Neoplasms Mediating Mitosis Modification Molecular Molecular Analysis Mutagenesis Nucleosomes Pathway interactions Phenotype Phosphorylation Post-Translational Protein Processing Post-Translational Regulation Protein Tyrosine Kinase Proteins Proteomics Regulation Repression Resolution Retinoblastoma Protein Route S phase Site Specificity Structure Substrate Cycling Substrate Interaction Testing Therapeutic Time Tumor Suppressor Proteins cancer cell cell growth chromatin remodeling cyclin F design inhibitor molecular imaging neoplastic cell novel novel therapeutic intervention programs promoter protein function protein protein interaction reconstitution recruit refractory cancer structural biology therapeutically effective ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Activation of E2F transcription factors is the most downstream event in the retinoblastoma protein (Rb) tumor suppressor pathway, which controls entry into the cell cycle and proliferation. E2F stimulates expression of genes needed for DNA synthesis during S phase and for further progression into mitosis. Inactivation of Rb and aberrant activation of the E2F-controlled transcription program is a hallmark of cancer. While Rb repression of E2F has been extensively characterized, little is known regarding how E2F activates transcription and how additional regulatory mechanisms control E2F function. Here we explore the structural mechanisms underlying the function and posttranslational regulation of E2F. Our first aim is to determine how E2F associates with chromatin and influences chromatin architecture to induce gene expression. We will use structural, biochemical, and cellular assays to investigate how E2F binds nucleosomes and how those interactions are critical for modulating chromatin architecture as cells activate the transcription program for S phase entry. Our second aim is to identify novel E2F posttranslational modifications and how modifications including phosphorylation and acetylation modulate E2F association with chromatin and co-activator proteins. Our third aim is to reveal how E2F proteins are recognized by the E3 ligase adaptor protein Cyclin F (CycF) for ubiquitylation and degradation. A structural and cell biology approach will be applied to define the CycF-binding motif, and we will test the hypothesis that chemical inhibition of CycF can deregulate the cell cycle in model cancer cells. In collaboration with the other program projects and cores, our study will provide unprecedented molecular analysis of E2F function and regulation. Our experimental results will provide foundational knowledge that can be applied to design new therapeutic strategies that target E2F activity in diverse cancers.

项目总结