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The role of the LZTR1 ubiquitin ligase in stem cells and cancer

LZTR1 泛素连接酶在干细胞和癌症中的作用

基本信息

批准号：
9262886
负责人：
Antonio Iavarone
金额：
$ 38.31万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262886
关键词：
Adopted Applications Grants BTB/POZ Domain Biochemical Biological Biological Process Biology Brain Brain Neoplasms Cell model Cells Chromosomal translocation Code Complex Copy Number Polymorphism Cullin Proteins Data Data Set Development Dissection Ensure Event Foundations Gene Dosage Genes Genetic Glioblastoma Glioma Goals Growth Hereditary Disease Human Impairment In Vitro Individual Insertional Mutagenesis Knock-out Knockout Mice Ligase Link Location Maintenance Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediating Mitochondria Modeling Molecular Mouse Strains Mus Mutation Nervous system structure Neurons Normal Cell Orphan Pathogenesis Play Point Mutation Proteins Proteolysis Recruitment Activity Reporting Role Salvelinus Sampling Set protein Sleeping Beauty Specificity Stem cells Substrate Domain Suppressor Genes System Technology Tertiary Protein Structure Time Tumor Initiators Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Validation Variant Work actionable mutation base cancer cell cancer initiation cullin-3 follow-up genetic analysis genetic regulatory protein in vivo innovation loss of function loss of function mutation mouse model multicatalytic endopeptidase complex nerve stem cell neurodevelopment next generation sequencing novel novel therapeutic intervention prevent protein complex protein function public health relevance scaffold self-renewal teration tumor tumor growth tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): In the genetic analysis of human cancer, focal gene copy number variation (CNV) and point mutations provide exquisite information on candidate driver genes by pinpointing their exact location. Recently, we conducted a large-scale analysis in which we integrated somatic point mutations and focal CNV information in a single framework to nominate new driver genes implicated in glioblastoma multiforme (GBM), one of the most aggressive types of human cancer. The top-ranking gene that emerged from this analysis is LZTR1, which codes for the substrate adaptor of a Cullin-3 (Cul3) ubiquitin ligase complex for which the substrates still await discovery. In GBM, LZTR1 is targeted by loss-of-function mutations and focal deletions, thus behaving as a new tumor suppressor gene, a notion recently confirmed in other tumors. From a mechanistic standpoint, we have discovered the unexpected capacity of LZTR1 to impair self-renewal and growth of the most aggressive cellular subpopulation in human GBM, the glioma stem cells (GSCs). The central objective of this proposal is to identify and functionally characterize the substrates of the LZTR1 ubiquitin ligase complex and decipher how mechanistically LZTR1 operates to prevent tumor development in normal neural cells. Our overarching hypothesis is that the LZTR1-Cul3 protein complex suppresses tumor growth through the regulated proteolysis of a particular set of substrates. Our preliminary data have already identified and validated a set of proteins with recognized mitochondrial activities as new LZTR1 substrates. Together with our recent observation that LZTR1 localizes at mitochondria, these results are exciting new findings that link alterations of LZTR1 to deregulation of mitochondrial functions in cancer. In Aim 1, the LZTR1 substrates will be comprehensively identified from a novel mass spectrometry-based technology that has already successfully recognized exciting, new substrate candidates of LZTR1. The functional validation of the substrates will be pursued in highly relevant cellular models directly generated from primary human GBM and will be related to the landscape of mutations of LZTR1 discovered in human cancer. In Aim 2, we will determine the normal activity of LZTR1 in the brain and model human GBM harboring inactivating mutations of LZTR1 in a new genetic mouse model in which the LZTR1 gene is conditionally knocked out in the nervous system. We will also use the Sleeping Beauty insertional mutagenesis system to identify the genetic alterations that cooperate with loss of LZTR1 for brain tumorigenesis.