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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（由申请人提供）：SCF (SKP1-Cullins-F box protein) E3泛素连接酶是最大的E3连接酶家族，可促进各种关键调控蛋白的泛素化和降解，从而控制许多重要的生物学过程，如细胞凋亡、细胞周期进程、DNA复制、胚胎发生和肿瘤发生。SCF由4个组分组成，包括支架蛋白cullin-1、接头蛋白SKP1、RING蛋白RBX1或RBX2和F-box蛋白。在哺乳动物细胞中，具有69个成员的F-box蛋白是决定SCF e3特异性的底物识别亚基。虽然多种蛋白底物已被表征良好的F-box蛋白之一ßTrCP， FBXW7或SKP2鉴定，但关于F-box蛋白是否以及如何相互调节却知之甚少。我们的初步数据表明：1)致癌的F-box蛋白TrCP与一个尚未被充分表征的F-box蛋白FBXW2结合，促进其泛素化和降解；2) FBXW2反过来与致癌的F-box蛋白SKP2结合，促进其泛素化和降解；3) FBXW2对肺癌细胞具有抑瘤作用；4)在人非小细胞肺癌组织中发现了FBXW2的一些功能获得性突变；5) β-TrCP、FBXW2、SKP2在肺癌组织中表达呈负相关，与患者生存有关。虽然β-TrCP和SKP2是被充分研究的具有致癌活性的F-box蛋白，但它们在细胞增殖和存活方面是否以及如何相互调节是完全未知的。本研究的目的是通过体外细胞培养和体内转基因小鼠模型，了解FBXW2如何介导和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如何在肺肿瘤发生中作为一种新的肿瘤抑制因子，并阐明其作用机制。中心假设是三个F- box蛋白，βTrCP-FBXW2-SKP2形成一个癌基因-肿瘤抑制因子-癌基因轴，相互调节以控制细胞增殖和肺肿瘤发生。为了验证我们的中心假设，我们提出了三个具体目标：1)将FBXW2表征为β-TRCP的新型底物；2)鉴定FBXW2为SKP2降解的新型E3连接酶；3)表征Fbxw2是一种新的抗肺肿瘤发生的肿瘤抑制因子。相关性:本研究的成功完成将从机制上阐明三种F-box蛋白如何通过相互靶向降解来调节肺癌细胞的增殖，两种致癌的F-box蛋白ß-TrCP和SKP2如何通过抑瘤F-box蛋白FBXW2相互对话，以及FBXW2如何在肺中作为肿瘤抑制因子。从而阐明了一种新的肺肿瘤发生机制，并为未来肺癌治疗中生物标志物的开发提供了有吸引力的靶点。

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）

Inactivation of SAG E3 ubiquitin ligase blocks embryonic stem cell differentiation and sensitizes leukemia cells to retinoid acid.

DOI：
10.1371/journal.pone.0027726
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Tan M;Li Y;Yang R;Xi N;Sun Y
通讯作者：
Sun Y

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

DOI：
10.18632/oncotarget.740
发表时间：
2012-11
期刊：
Oncotarget
影响因子：
0
作者：
Wang Z;Inuzuka H;Zhong J;Liu P;Sarkar FH;Sun Y;Wei W
通讯作者：
Wei W

SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation.

SAG/RBX2 E3 连接酶与 UBCH10 和 UBE2S E2 复合物通过 K11 连接泛素化 β-TrCP1 进行降解。

DOI：
10.1038/srep37441
发表时间：
2016-12-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Kuang P;Tan M;Zhou W;Zhang Q;Sun Y
通讯作者：
Sun Y

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

Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis.