Core B: Proteomics Core.

核心 B：蛋白质组学核心。

基本信息

批准号：
10597203
负责人：
PETER Kent JACKSON
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/10597203
关键词：
Affect Affinity Chromatography Automobile Driving Binding Biological Markers Biology CDK4 gene Cancer Control Cell Cycle Regulation Cell Proliferation Cell Survival Cell division Cells Chromatin Clinical Communities Complex Core Protein Coupled Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Cytoplasm DNA Damage Data Databases Dependence E2F transcription factors Ensure Enzymes 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 clinical efficacy data communication experimental study extracellular inhibitor insight interest malignant breast neoplasm mass spectrometer melanoma member mutant nucleocytoplasmic transport paralogous gene phosphoproteomics posttranscriptional protein complex protein protein interaction response transcription factor

Affect Affinity Chromatography Automobile Driving Binding Biological Markers Biology CDK4 gene Cancer Control Cell Cycle Regulation Cell Proliferation Cell Survival Cell division Cells Chromatin Clinical Communities Complex Core Protein Coupled Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Cytoplasm DNA Damage Data Databases Dependence E2F transcription factors Ensure Enzymes 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 clinical efficacy data communication experimental study extracellular inhibitor insight interest malignant breast neoplasm mass spectrometer melanoma member mutant nucleocytoplasmic transport paralogous gene phosphoproteomics posttranscriptional protein complex protein protein interaction response transcription factor

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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.

项目摘要许多致命的癌症在以细胞周期蛋白D，CDK4或CDK6形式驱动的途径中显示突变，它们的抑制作用蛋白质，RB视网膜细胞瘤蛋白和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也具有转录无关的影响细胞分裂和生存的活动。相当大的兴趣是由细胞周期蛋白D/CDK4抑制剂palbociclib，这表明该途径的其他组成部分可能是抑制剂，或者新目标可能存在于途径内。尽管蛋白质组学工作确定了蛋白质与途径成分，关键分子效应子和RB途径的调节剂相关联调节这些因素的翻译后修饰（PTM）尚不清楚。在这里，我们将首先关注系统地识别（1）在G1/s进展过程中观察到的蛋白质，PTM和信号依赖性；（2）确定哪些途径成分对shot弹枪和磷蛋白质组学对palbociclib做出反应；（3）定义细胞周期蛋白D-CDK4/6和RB/E2F成分的核和细胞质调节复合物；（4）建立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组件之间相互作用的特异性；（6）鉴定在该途径的组件中发现的TCGA癌病变。这些测量和蛋白质组学核心执行的扰动将组装到PTM和蛋白质蛋白质网络中相互作用（PPI），推动了这一关键癌症途径的新假设。