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p190 RhoGAP signaling in epithelial oncogenesis

p190 RhoGAP 信号在上皮肿瘤发生中的作用

基本信息

批准号：
10080030
负责人：
STEEN HENNING HANSEN
金额：
$ 40.49万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-03 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080030
关键词：
Adenocarcinoma Adherens Junction Anoikis Area Attenuated Bioinformatics Cadherins Cancer cell line Carcinoma Catalogs Cell Communication Cell-Cell Adhesion Cells Censuses Collaborations Contact Inhibition Data E-Cadherin Endometrial Carcinoma Epithelial Epithelial Cells Family Future GRLF1 gene Gastrointestinal tract structure Gene Expression Gene Mutation Genes Genetic Transcription Genome Genomic Segment Goals Human Hydrolysis In Vitro Inhibition of Cell Proliferation Institutes Link Literature Loss of Heterozygosity Lung MDCK cell Malignant Epithelial Cell Malignant Neoplasms Mediating Mutate Mutation Oncogenes Oncogenic Oncology Oncoproteins Organ Pathway interactions Play Proteins Publishing Renal Cell Carcinoma Role Sampling Signal Pathway Signal Transduction Squamous cell carcinoma Testing Tissues Transcription Coactivator Tumor Suppressor Proteins Uncertainty Validation Work cancer genome cell type driver mutation genome-wide improved in vitro testing in vivo insight mRNA sequencing novel paralogous gene personalized cancer therapy precision oncology reproductive tract rho rho GTPase-activating protein transcription factor transcriptome sequencing tumor tumorigenesis unpublished works

项目摘要

ABSTRACT Recent analyses of gene mutations in human cancer unexpectedly identified ARHGAP35 encoding p190A RhoGAP (p190A) as a highly mutated gene, i.e. top 30 pan-cancer. Mutations were particularly abundant in adenocarcinomas, including renal cell carcinoma. The mutation spectrum for ARHGAP35 is consistent with a role as tumor suppressor. Moreover the ARHGAP35 locus is located in a region of the genome that frequently is lost in cancer. However, bioinformatics data stop short of establishing the functional consequences of gene mutations. The scope of this proposal is therefore to define oncogenic capacities associated with loss of p190A expression and with naturally occurring ARHGAP35 mutations in human cancer. We have recently obtained results demonstrating that p190A and its paralog p190B - collectively termed p190 here - mediate contact inhibition of proliferation (CIP) in epithelial cells. We moreover conducted a genome wide RNA-seq analysis, and determined that p190 modulates expression of genes regulated by the YAP oncoprotein. YAP is a transcriptional co-activator of TEAD family transcription factors. The activity of YAP is controlled by the Hippo pathway, which is widely implicated in CIP. In Aim 1 we will define mechanisms whereby p190 impacts Hippo signaling and CIP. To this end, we will (i) test whether Rho proteins are required and/or sufficient to promote CIP downstream of p190; (ii) determine if p190 signals through the canonical and/or non-canonical Hippo pathways; (iii) establish if p190 impacts YAP- TEAD-mediated gene expression; and (iv) determine if apparent redundancy between p190A and p190B in epithelial cells is context-dependent. In Aim 2 we will elucidate the function of p190 at adherens junctions (AJs), which play essential roles in promoting CIP through the Hippo pathway. In this aim, we will (i) test a role for p190 to activate the Hippo pathway upon formation of nascent AJs; (ii) establish whether p190 is required for E-cadherin to restore Hippo signaling in carcinoma cells; (iii) define a role for p190 in anoikis, a tumor suppressor mechanism that is modulated by both AJs and the Hippo pathway; and (iv) elucidate if an interaction between p190 and p120- catenin is required for Hippo signaling and CIP. In Aim 3 we will in collaboration with Dr. Gad Getz of the Broad Institute, analyze human tumors with ARHGAP35 mutation for (i) loss-of-heterozygosity; (ii) expression of YAP regulated genes; and (iii) co-mutation and exclusivity data. Next, we will determine the effects of naturally occurring ARHGAP35 mutations on p190A RhoGAP activity, as well as Hippo signaling and CIP. Finally, we will test in vitro and in vivo if expression of exogenous p190A attenuates oncogenic capacities of human cancer cell lines with no or very low levels of endogenous p190A, and if such effects are dependent GAP activity and/or on Hippo signaling. These efforts are essential to elucidate the utility of targeting Rho signaling in future personalized oncology therapy.

摘要

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome editing using FACS enrichment of nuclease-expressing cells and indel detection by amplicon analysis.

使用FACS富集表达核酸酶的细胞的基因组编辑，并通过扩增子分析进行INDEL检测。

DOI：
10.1038/nprot.2016.165
发表时间：
2017-03
期刊：
Nature protocols
影响因子：
14.8
作者：
Lonowski LA;Narimatsu Y;Riaz A;Delay CE;Yang Z;Niola F;Duda K;Ober EA;Clausen H;Wandall HH;Hansen SH;Bennett EP;Frödin M
通讯作者：
Frödin M

p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity.

DOI：
10.1083/jcb.201710058
发表时间：
2018-09-03
期刊：
The Journal of cell biology
影响因子：
0
作者：
Frank SR;Köllmann CP;Luong P;Galli GG;Zou L;Bernards A;Getz G;Calogero RA;Frödin M;Hansen SH
通讯作者：
Hansen SH

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma.

DOI：
10.1053/j.gastro.2017.09.008
发表时间：
2017-12
期刊：
Gastroenterology
影响因子：
29.4
作者：
Engelholm LH;Riaz A;Serra D;Dagnæs-Hansen F;Johansen JV;Santoni-Rugiu E;Hansen SH;Niola F;Frödin M
通讯作者：
Frödin M