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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：
10197175
负责人：
SHARON Y. R. DENT
金额：
$ 39.96万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197175
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 refractory cancer 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.

项目摘要 USP 22泛素特异性蛋白酶的过表达与多种类型的肿瘤患者预后不良有关。治疗抗性癌症，导致其被指定为“癌症死亡”基因标记的成员。然而，USP 22在正常细胞中的功能尚不清楚，因此尚不清楚这种酶如何有助于癌症的形成或发展。USP 22是去泛素化模块的催化亚基 (DUB)在高度保守的佐贺复合物中，它调节基因表达过程中的多个步骤。转录。在上一个资助期，我们产生了USP 22敲除小鼠，以进一步确定其体内功能，我们发现USP 22在胎盘发育过程中对胎儿血管系统的发育起作用，迷宫RNA-seq揭示了TGF-β和受体酪氨酸激酶（RTK）途径（例如c-Met/HGFR， Errb 2和PDGFR）在USP 22突变胎盘中下调。这些途径不仅至关重要，对于正常胎盘发育，但也对于肿瘤发生，并且TCGA数据的检查揭示了这些在过表达USP 22的肿瘤中，信号通路被上调。我们假设USP 22调节这些控制正常细胞生长和行为的途径，以及USP 22表达的异常导致与疾病相关的信号通路畸变。为了验证这一假设，在Usp 22突变体中TGF-β和RTK信号传导变化的机制基础上，我们将使用小鼠和细胞携带USP 22的条件性无效、“floxed”等位基因或条件性过表达等位基因，以1）定义特异性胎盘中受USP 22损失影响的细胞谱系2）确定USP 22的直接分子靶点和3）确定USP 22过表达是否足以驱动小鼠中的异常TGF-β 1或RTK信号传导。这些研究将为USP 22在信号传导、发育和免疫调节中的功能建立新的范例。疾病从长远来看，我们的发现将为先兆子痫和癌症的病因学提供新的见解，并且它们可以提供治疗或预防这些病症的新途径。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Complex functions of Gcn5 and Pcaf in development and disease.

DOI：
10.1016/j.bbagrm.2020.194609
发表时间：
2021-03
期刊：
Biochimica et biophysica acta. Gene regulatory mechanisms
影响因子：
0
作者：
Koutelou E;Farria AT;Dent SYR
通讯作者：
Dent SYR

Histone-modifying enzymes: regulators of developmental decisions and drivers of human disease.

组蛋白修饰酶：发育决策的调节剂和人类疾病的驱动因素。

DOI：
10.2217/epi.12.3
发表时间：
2012-04
期刊：
Epigenomics
影响因子：
3.8
作者：
Butler JS;Koutelou E;Schibler AC;Dent SY
通讯作者：
Dent SY

Now open: Evolving insights to the roles of lysine acetylation in chromatin organization and function.

DOI：
10.1016/j.molcel.2021.12.004
发表时间：
2022-02-17
期刊：
Molecular cell
影响因子：
16
作者：
Chen YC;Koutelou E;Dent SYR
通讯作者：
Dent SYR

Usp22 Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice.

DOI：
10.3390/cancers13174276
发表时间：
2021-08-25
期刊：
Cancers
影响因子：
5.2
作者：
Kuang X;McAndrew MJ;Mustachio LM;Chen YC;Atanassov BS;Lin K;Lu Y;Shen J;Salinger A;Macatee T;Dent SYR;Koutelou E
通讯作者：
Koutelou E

USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B.

DOI：
10.1016/j.celrep.2016.10.076
发表时间：
2016-11-22
期刊：
Cell reports
影响因子：
8.8
作者：
Lan X;Atanassov BS;Li W;Zhang Y;Florens L;Mohan RD;Galardy PJ;Washburn MP;Workman JL;Dent SYR
通讯作者：
Dent SYR