Core B: Proteomics Core.

核心 B：蛋白质组学核心。

基本信息

批准号：
10332384
负责人：
PETER Kent JACKSON
金额：
$ 27.65万
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/10332384
关键词：
Affect Affinity Chromatography Automobile Driving Binding Biology CDK4 gene Cell Cycle Regulation Cell Proliferation Cell Survival Cell division Cells Chromatin Clinical Communities Complex Core Protein Coupled Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A DNA Damage Data Data Analyses Databases Dependence E2F transcription factors Ensure Family G1/S Transition Gene Expression Genes Genetic Transcription Global Change Grant Growth Growth Factor Guidelines Head and Neck Cancer Knock-out Lead Lesion Link MEKs Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of pituitary gland Mass Spectrum Analysis Measurement Mitochondria Molecular Mutation Nuclear Output Pathway interactions Patients Pharmaceutical Preparations Post-Translational Protein Processing Protein Analysis Protein Structure Initiative Proteins Proteomics Protocols documentation Reporting Retinoblastoma Protein Running Shotguns Side Signal Transduction Site Specificity Standardization Techniques Testing The Cancer Genome Atlas Therapeutic Transcriptional Regulation Work base cancer cell clinical efficacy data communication enzyme pathway experimental study extracellular inhibitor insight interest malignant breast neoplasm mass spectrometer melanoma member mutant nucleocytoplasmic transport paralogous gene phosphoproteomics protein complex protein protein interaction response targeted biomarker transcription factor

项目摘要

Project Summary Many deadly cancers show mutations in a pathway driven by forms of cyclin D, Cdk4 or Cdk6, their inhibitory proteins, the Rb retinoblastoma protein, and the E2F transcription factors. These include breast cancer, melanoma, head and neck cancer, esophageal and pituitary cancers. We know that Rb suppresses E2F transcription factors to control genes critical for cell proliferation, but Rb also has transcription-independent activities that impact cell division and survival. Considerable interest is driven by the clinical efficacy of the cyclin D/Cdk4 inhibitor palbociclib, suggesting that additional components of this pathway may be targets of the inhibitor, or that new targets may reside within the pathway. Despite proteomic work identifying proteins that associate with pathway components, the key molecular effectors and regulators of the Rb pathway and protein post-translational modifications (PTMs) that regulate these factors remain unclear. Here we will focus first on systematically identifying (1) the proteins, PTMs, and signal dependencies observed during G1/S progression; (2) identifying which pathway components respond to Palbociclib by shotgun and phosphoproteomics; (3) defining nuclear and cytoplasmic regulated complexes for Cyclin D-Cdk4/6 and Rb/E2F components; (4) building protein interaction networks to link PTMs to protein interactions and activity; (5) determining the specificity of interactions among paralogs of the Cdk4/6, Cyclin D1/2/3, Rb and E2F components; and (6) identifying TCGA cancer lesions found within components of this pathway. These measurements and perturbations performed by the Proteomics Core will be assembled into a network of PTMs and protein-protein interactions (PPIs), driving new hypotheses for this critical cancer pathway.

项目概要许多致命的癌症在由细胞周期蛋白 D、Cdk4 或 Cdk6 形式驱动的通路中表现出突变，它们的抑制作用蛋白、Rb 视网膜母细胞瘤蛋白和 E2F 转录因子。这些包括乳腺癌、黑色素瘤、头颈癌、食道癌和垂体癌。我们知道 Rb 抑制 E2F 转录因子控制对细胞增殖至关重要的基因，但 Rb 也具有转录独立性影响细胞分裂和存活的活动。其临床疗效引起了人们的极大兴趣 cyclin D/Cdk4 抑制剂 palbociclib，表明该途径的其他成分可能是抑制剂，或者新的靶标可能存在于该通路内。尽管蛋白质组学工作确定了蛋白质与通路成分、Rb 通路和蛋白质的关键分子效应器和调节器相关调节这些因素的翻译后修饰（PTM）仍不清楚。这里我们首先要关注的是系统地识别 (1) G1/S 进展期间观察到的蛋白质、PTM 和信号依赖性； (2) 通过鸟枪法和磷酸蛋白质组学鉴定哪些通路成分对 Palbociclib 有反应； (3) 定义 Cyclin D-Cdk4/6 和 Rb/E2F 成分的核和细胞质调节复合物； (4) 构建蛋白质相互作用网络，将 PTM 与蛋白质相互作用和活性联系起来； (5) 确定 Cdk4/6、Cyclin D1/2/3、Rb 和 E2F 成分的旁系同源物之间相互作用的特异性；和（6）识别该通路组成部分中发现的 TCGA 癌症病变。这些测量和蛋白质组学核心进行的扰动将被组装成 PTM 和蛋白质-蛋白质的网络相互作用（PPI），推动了这一关键癌症途径的新假设。