Defining USP22 Functions During Mammalian Development

定义哺乳动物发育过程中的 USP22 功能

基本信息

批准号：
9769094
负责人：
SHARON Y. R. DENT
金额：
$ 40.78万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769094
关键词：
Affect Alleles Behavior Biochemical Blood Vessels Breast Cancer Cell Catalytic Domain Cell Lineage Cell physiology Cells Cessation of life ChIP-seq Chorion Colon Carcinoma Complex Data Defect Deubiquitination Development Developmental Process Disease ERBB2 gene Endothelial Cells Enzymes Etiology Event Failure Fetal Development Fostering Funding GAB1 gene Gene Expression Profiling Genes Genetic Genetic Transcription Growth Histone H2B Immune Knockout Mice Labyrinth Link LoxP-flanked allele MET gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Mammary gland Molecular Molecular Analysis Molecular Target Morphology Mus Normal Cell Null Lymphocytes Oncogenes Oncogenic PDGFRB gene Pathway interactions Patient-Focused Outcomes Pericytes Phenotype Phosphoric Monoester Hydrolases Placenta Placentation Platelet-Derived Growth Factor Pre-Eclampsia Prevention Processed Genes Proteins Receptor Protein-Tyrosine Kinases Regulation Role SAGA Signal Pathway Signal Transduction Signaling Molecule TGFB1 gene TGFBR1 gene Testing The Cancer Genome Atlas Tissues Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenes Up-Regulation aggressive therapy arm blood vessel development cancer type disorder prevention embryonic stem cell experimental study fetal blood genetic signature growth factor receptor-bound protein 2 human disease in vivo insight interest malignant breast neoplasm malignant stomach neoplasm member mouse model mutant novel null mutation overexpression receptor response telomere therapy resistant transcription factor transcriptome sequencing tumor tumor growth tumor xenograft tumorigenesis ubiquitin-specific protease

项目摘要

Project Summary Overexpression of the USP22 ubiquitin specific protease is linked to poor patient outcome in multiple types of therapy resistant cancers, leading to its designation as a member of a `death from cancer' gene signature. However, the functions of USP22 in normal cells are not well defined, so it is not clear how this enzyme contributes to cancer formation or progression. USP22 is the catalytic subunit of the deubiquitination module (DUB) within the highly conserved SAGA complex, which regulates multiple steps in the process of gene transcription. In the last funding period, we generated USP22 null mice to further define its functions in vivo, and we discovered a role for USP22 in development of fetal vasculature during development of the placental labyrinth. RNA-seq reveals that TGF-beta and receptor tyrosine kinase (RTK) pathways (e.g. c-Met/HGFR, Errb2, and PDGFR) are down regulated in USP22 mutant placentas. These pathways are essential not only for normal placental development but also for tumorigenesis, and examination of TCGA data reveals that these pathways are up regulated in tumors that overexpress USP22. We hypothesize that USP22 regulates these pathways to control the growth and behavior of normal cells, and that aberrations in USP22 expression contributes to signaling pathway aberrations associated with disease. To test this hypothesis and to define the mechanistic basis of changes in TGF-beta and RTK signaling in Usp22 mutants, we will use mice and cells bearing a conditional null, `floxed' allele or a conditional overexpressing allele of USP22 to 1) Define specific cell lineages in the placenta affected by USP22 loss 2) Define direct molecular targets of USP22 and 3) Determine whether USP22 overexpression is sufficient to drive abnormal TGF-beta1 or RTK signaling in mice. These studies will establish new paradigms for the functions of USP22 in signaling, in development, and in disease. In the longer term, our findings will provide new insights to the etiology of preeclampsia and cancer, and they may provide new avenues for treatment or prevention of these conditions.

项目概要 USP22 泛素特异性蛋白酶的过度表达与多种类型的患者预后不良有关治疗耐药性癌症，导致其被指定为“癌症死亡”基因特征的成员。然而，USP22在正常细胞中的功能尚不清楚，因此尚不清楚这种酶是如何发挥作用的。有助于癌症的形成或进展。 USP22 是去泛素化模块的催化亚基 (DUB) 位于高度保守的 SAGA 复合体中，调节基因过程中的多个步骤转录。在上一个资助期间，我们生成了USP22 null小鼠以进一步定义其体内功能，我们发现了 USP22 在胎盘发育过程中胎儿血管系统发育中的作用迷宫。 RNA-seq 揭示了 TGF-β 和受体酪氨酸激酶 (RTK) 通路（例如 c-Met/HGFR、 Errb2 和 PDGFR) 在 USP22 突变胎盘中下调。这些途径不仅重要对于正常胎盘发育以及肿瘤发生，TCGA 数据的检查表明，这些在过度表达 USP22 的肿瘤中，信号通路上调。我们假设 USP22 调节这些控制正常细胞生长和行为的途径以及 USP22 表达的异常导致与疾病相关的信号通路异常。为了检验这个假设并定义 Usp22 突变体中 TGF-β 和 RTK 信号传导变化的机制基础，我们将使用小鼠和细胞带有条件无效、“floxed”等位基因或 USP22 的条件过表达等位基因 1) 定义特定的受 USP22 缺失影响的胎盘细胞谱系 2) 定义 USP22 的直接分子靶点和 3) 确定 USP22 过度表达是否足以驱动小鼠中异常的 TGF-β1 或 RTK 信号传导。这些研究将为 USP22 在信号传导、发育和功能方面的功能建立新的范例。疾病。从长远来看，我们的研究结果将为先兆子痫和癌症的病因学提供新的见解，它们可能为治疗或预防这些疾病提供新的途径。