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Project 1: Determine the mechanisms Cyclin D-Cdk4/6 uses to drive cell proliferation

项目 1：确定 Cyclin D-Cdk4/6 驱动细胞增殖的机制

基本信息

批准号：
10867552
负责人：
Jan M Skotheim
金额：
$ 6.67万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10867552
关键词：
Acute Lymphocytic Leukemia Address Alanine Alleles Binding Biochemistry Biological Assay Biological Sciences C-terminal Cancer Control Cancer Model Cell Cycle Arrest Cell Line Cell Proliferation Cell division Cells Clinical Trials Complex Cyclin D1 Cyclin-Dependent Kinases Cyclins DNA Data Docking Engineering Enzymes Fluorescence Polarization Fluorescence Resonance Energy Transfer G1/S Transition Goals Human In Vitro Knowledge Libraries Location Malignant Neoplasms Malignant neoplasm of brain Molecular Mus Mutation Neuroblastoma Peptides Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Property Protein Kinase Proteomics Reagent Regulation Retinoblastoma Protein Role Site Structure Testing Therapeutic Xenograft procedure alpha helix analog cancer therapy chemical genetics delivery vehicle design experimental study genetic approach improved in vitro testing in vivo inhibitor malignant breast neoplasm molecular imaging mouse model phosphoproteomics small molecule small molecule libraries structural biology targeted cancer therapy targeted treatment therapeutic target tool tumor tumor growth

项目摘要

PROJECT SUMMARY Human cell division is regulated at the G1/S transition before DNA is replicated. The primary drivers of cells through the G1/S transition are the cyclin-dependent kinases Cdk4 and Cdk6 in complex with D-type cyclins. The goal of this project is to determine the mechanisms that Cyclin D-Cdk4/6 complexes use to drive cell division. This is important for cancer because Cdk4/6 activity is elevated in many cancers including breast cancers, brain cancers, acute lymphoblastic leukemia, and neuroblastoma tumors. Inhibiting Cyclin D-Cdk4/6 is therefore a promising avenue for therapies targeting these cancers. Here, we propose to determine how Cyclin D-Cdk4/6 drives the G1/S transition. First, we will do this by identifying all the targets of Cyclin D-Cdk4/6 kinases in cells using a chemical genetic approach. Second, we will determine the molecular mechanism Cyclin D-Cdk4/6 uses to dock and phosphorylate its primary target, the retinoblastoma protein Rb. In preliminary data, we discovered that Cyclin D binds an alpha helix at the C-terminus of Rb. We now aim to determine the location on Cyclin D that docks Rb’s C-terminal helix using a combination of in vitro biochemistry and structural biology approaches. We propose to use knowledge of this docking interaction to develop a tool compound that disrupts the interaction and arrests the cell cycle. This will allow testing of the importance of the interactions in cells and provides a proof-of-principle that disrupting this interaction could be used in targeted cancer therapeutics. We will pursue two directions to identify a tool compound. First, we will develop a peptide inhibitor based on Rb’s C-terminal helix. Second, we will screen a small molecule library using a FRET assay. Taken together, the proposed experiments will provide an in-depth analysis of the Cyclin D-Rb interaction and will determine how it drives cell division. The broader impact of this study of the Cyclin D molecular docking mechanism and identification of Cyclin D-Cdk4/6 substrates may be the identification of new small molecules that improve cancer therapy.

项目总结