The role of FBXW2 as a novel lung tumor suppressor that cross-talks with oncogenic beta-TrCP and SKP2

FBXW2 作为一种新型肺肿瘤抑制因子与致癌 β-TrCP 和 SKP2 相互作用的作用

基本信息

批准号：
10017668
负责人：
Meredith A Morgan
金额：
$ 36.81万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-11 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017668
关键词：
Adaptor Signaling Protein Affect Apoptosis Binding Biological Biological Process CUL1 gene Cell Culture Techniques Cell Cycle Progression Cell Proliferation Cell Survival DNA biosynthesis Data Embryonic Development F Box Domain F-Box Proteins FBXW7 gene Family Future Growth Human In Vitro Lung Lung Neoplasms Malignant neoplasm of lung Mammalian Cell Mediating Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Patients Phosphotransferases Proteins Proteomics RBX1 gene Role SKP2 gene Scaffolding Protein Signal Pathway Signaling Molecule Skp1-Cullin-F-Box Proteins Skp2 Proteins Specificity Testing Tissues Tumor Suppressor Genes Tumor Suppressor Proteins beta-Transducin Repeat-Containing Proteins biomarker development cancer cell gain of function genetic regulatory protein in vivo lung tumorigenesis member mouse model mutant novel p19(SKP1) Protein protein degradation public health relevance targeted biomarker tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): SCF (SKP1-Cullins-F box protein) E3 ubiquitin ligase is the largest family of E3 ligases that promote the ubiquitylation and degradation of various key regulatory proteins, thus controlling many important biological processes, such as apoptosis, cell cycle progression, DNA replication, embryogenesis and tumorigenesis. SCF consists of 4 components, including a scaffold protein cullin-1, an adaptor protein SKP1, a RING protein RBX1 or RBX2 and an F-box protein. The F-box protein with 69 members in mammalian cells is the substrate- recognizing subunit that determines the specificity of SCF E3s. While a variety of protein substrates have been identified by one of well-characterized F-box proteins ßTrCP, FBXW7, or SKP2, very little is known as to whether and how F-box proteins regulate each other. Our preliminary data showed that 1) oncogenic F-box protein TrCP binds to yet a poorly characterized F-box protein FBXW2 to promote its ubiquitylation and degradation; 2) FBXW2 in turn binds to oncogenic F-box protein SKP2 to promote its ubiquitylation and degradation; 3) FBXW2 has tumor suppressive function against lung cancer cells; 4) A number of gain-of- function FBXW2 mutations were found in human non-small cell lung carcinoma tissues; and 5) reversed correlation in expression among β-TrCP, FBXW2 and SKP2 exists in lung cancer tissues, which is associated with patient survival. Although β-TrCP and SKP2 are well-studied F-box proteins with oncogenic activity, whether and how they regulate each other with regard to cell proliferation and survival is totally unknown. The objectives of this proposed study is to understand how FBXW2 mediates and modulates the activity of two well-known oncogenic F-box proteins, β-TrCP and SKP2, and how FBXW2 acts as a novel tumor suppressor in lung tumorigenesis using both in vitro cell culture and in vivo genetically modified mouse models with elucidation of its mechanism of action. The central hypothesis is that three F- box proteins, βTrCP-FBXW2-SKP2 form an oncogene-tumor suppressor-oncogene axis that regulates each other to control cell proliferation and lung tumorigenesis. Three specific aims are proposed to test our central hypothesis by 1) characterizing FBXW2 as a novel substrate of β-TRCP; 2) characterizing FBXW2 as a novel E3 ligase for SKP2 degradation; and 3) characterizing Fbxw2 as a novel tumor suppressor against lung tumorigenesis. Relevance: Successful completion of this proposed study will mechanistically elucidate how three F-box proteins regulate proliferation of lung cancer cells by targeting each other for degradation, and how two oncogenic F-box proteins ß-TrCP and SKP2 talk with each other via a tumor suppressive F-box protein FBXW2, and how FBXW2 acts as a tumor suppressor in the lung, thus elucidating a novel mechanism of lung tumorigenesis and providing attractive targets for future biomarker development in lung cancer management.

描述（由应用提供）：SCF（SKP1碳蛋白-F盒蛋白）E3泛素连接酶是E3连接酶的最大家族，可促进各种关键调节蛋白的泛素化和降解，从而控制许多重要的生物学过程，例如凋亡，细胞周期进展，DNA重复，embryation，Embryegen和Tumorige剂。 SCF由4个成分组成，包括脚手架蛋白Cullin-1，衔接蛋白SKP1，环蛋白RBX1或RBX2和F-box蛋白。哺乳动物细胞中有69个成员的F-box蛋白是确定SCF E3特异性的亚基的底物。尽管特征良好的F-box蛋白β，FBXW7或SKP2鉴定了多种蛋白质底物，但对于F-box蛋白是否以及如何相互调节，很少知道。我们的初步数据显示4）在人类非小细胞肺癌组织中发现了许多功能FBXW2突变。 5）在肺癌组织中存在β-TRCP，FBXW2和SKP2之间表达的相关性，这与患者的生存有关。尽管β-TRCP和SKP2是具有致癌活性的经过良好研究的F-box蛋白，但它们是否以及如何相互调节在细胞增殖和生存方面是完全未知的。这项拟议的研究的目标是了解FBXW2如何介导并调节两种众所周知的致癌F-box蛋白β-trcp和SKP2的活性，以及FBXW2如何在肺部肿瘤中使用遗传培养物和遗传模型的模型在肺部肿瘤中起新型肿瘤抑制作用。中心假设是三个F-box蛋白β-TRCP-FBXW2-SKP2形成了一种肿瘤 - 抑制抑制剂 - 依符轴，它们相互调节以控制细胞增殖，并提出了三个特定目标，以表征我们的中心假设，以1）表征FBXW2作为新型substrateβ-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-蛋白酶; 2）将fbxw2表征为新型的E3连接酶，用于SKP2降解； 3）将FBXW2表征为一种针对肺肿瘤发生的新型肿瘤抑制。 Relevance: Successful completion of this proposed study will mechanistically elucidate how three F-box proteins regulate proliferation of lung Cancer cells by targeting each other for degradation, and how two oncogenic F-box proteins ß-TrCP and SKP2 talk with each other via a tumor suppressive F-box protein FBXW2, and how FBXW2 acts as a tumor suppressor in the lung, thus elucidating a肺肿瘤发生的新型机制，为肺癌管理中未来生物标志物的发展提供了有吸引力的靶标。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cytidine Deaminase APOBEC3A Regulates PD-L1 Expression in Cancer Cells in a JNK/c-JUN-Dependent Manner.

DOI：
10.1158/1541-7786.mcr-21-0219
发表时间：
2021-09
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Zhao K;Zhang Q;Flanagan SA;Lang X;Jiang L;Parsels LA;Parsels JD;Zou W;Lawrence TS;Buisson R;Green MD;Morgan MA
通讯作者：
Morgan MA

Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.