Nuclear functions of catenin subfamilies

连环蛋白亚家族的核功能

• 批准号: 9296597
• 负责人: PIERRE D MCCREA
• 金额: $ 10.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296597
• 关键词: Address; Amphibia; Animal Model; Animals; Binding; Bioinformatics; Cell Differentiation process; Cell Line; Cell Nucleus; Cells; ChIP-seq; Communities; Complex; Development; Disease; Disease Outcome; Disease Progression; ETV1 gene; Embryo; Embryonic Development; Evaluation; Family; Family member; Genes; Health; Homeostasis; Human; Human Pathology; Instruction; Knowledge; Ligands; Literature; Mammalian Cell; Modeling; Molecular; Mus; Names; Nature; Nuclear; Pathologic; Pathology; Pathway interactions; Play; Positioning Attribute; Protein Isoforms; Proteins; Rana; Regulation; Role; Signal Transduction; Stem Cell Development; Stem cells; System; Testing; Time; Tissues; Transcription Coactivator; Transducers; Tumor Suppression; Vertebrates; Work; Xenopus; base; beta catenin; cell behavior; comparative; embryonic stem cell; genome-wide; genome-wide analysis; human disease; in vivo; insight; novel; plakophilins; pluripotency; programs; relating to nervous system; research study; response; transcription factor; transcriptome sequencing; tumor progression; whole genome

DESCRIPTION (provided by applicant): What are the roles of vertebrate catenins in the nucleus, and how do they contribute to shared or distinct developmental or disease outcomes? In sharp contrast to the dominant focus upon beta-catenin in the existing literature, we will probe the nuclear roles of p120-catenin and plakophilin3-catenin. Each is poorly understood despite playing key roles in development and human pathology. We recently revealed that p120 and additional catenins are regulated via Wnt-pathway mechanisms known to act upon beta-catenin. We thus ask if Wnt (or other) signals may involve a larger catenin network whose nuclear activities have yet to be defined. Providing a strong entry point to the nuclear functions of these "other catenins", we recently discovered two novel complexes that respectively involve p120-catenin and plakophilin3-catenin. The first complex is of p120-catenin with REST/CoREST (Aim 1), and the second is of plakophilin3-catenin with ETV1 (Aim 2). Given the importance of REST/CoREST and ETV1 in stem cells, development and pathology, an understanding of these complexes will have an impact upon multiple scientific fields. Finally, to provide the scientific community with a much needed but currently absent overview of catenin nuclear functions, we will undertake the first genome-wide comparative evaluation of representative catenins from three distinct subfamilies (Aim 3). We will employ Xenopus embryos and mammalian cell lines for mechanistic and functional studies in Aims 1 and 2, and mouse embryo stem cells (mESCs) for our genome wide analysis of nuclear catenins in Aim 3. Our Hypothesis is that catenins of the p120- and plakophilin-subfamilies, in common with the much better known beta-catenin, act in networked nuclear capacities during vertebrate development and disease. Aim 1. Reveal nuclear functions of the novel p120-catenin:REST/CoREST complex. Aim 2. Reveal nuclear functions of the novel Pkp3-catenin:ETV1 complex. Aim 3. Genome-wide analysis of p120-, plakophilin3-, and beta-catenin nuclear functions. The key nature of beta-catenin and canonical Wnt signaling in development and human disease is firmly established, yet the nuclear contributions of additional catenins, that likewise play key roles in human embryogenesis and disease, is in contrast poorly understood. By in-depth examination of the nuclear roles of two novel catenin complexes we have discovered (respectively involving p120- and Pkp3-catenin), as well as revealing these catenins' nuclear roles on a much wider whole-genome level, we will produce the first understanding of what we hypothesize is an integrated network of catenin functions needed to maintain health.

描述（由申请人提供）：脊椎动物在细胞核中的作用是什么，它们如何有助于共享或独特的发育或疾病结果？与现有文献中对β-catenin的主要关注相比，我们将调查 P120-catenin和plakophilin3-catenin的核作用。尽管在发育和人类病理学中扮演了关键的作用，但每个人都对每个人都了解不佳。我们最近透露，P120和其他Catenin是通过已知对β-catenin作用的WNT-Pathway机制来调节的。因此，我们询问WNT（或其他）信号是否可能涉及尚未定义的核活动的较大的Catenin网络。为这些核能提供了强大的切入点 我们最近发现了两种新型复合物，分别涉及P120-catenin和plakophilin3-catenin。第一个复合物是带有静息/corest的P120-catenin（AIM 1），而第二个是带有ETV1的plakophilin3-catenin（AIM 2）。鉴于静息/Corest和ETV1在干细胞中的重要性，发育和病理学，对这些复合物的理解将对多个科学领域产生影响。最后，为了为科学界提供急需但目前缺乏Catenin核功能的概述，我们将对来自三个不同的亚科的代表性catenin进行首次全基因组比较评估（AIM 3）。 We will employ Xenopus embryos and mammalian cell lines for mechanistic and functional studies in Aims 1 and 2, and mouse embryo stem cells (mESCs) for our genome wide analysis of nuclear catenins in Aim 3. Our Hypothesis is that catenins of the p120- and plakophilin-subfamilies, in common with the much better known beta-catenin, act in networked nuclear capacities during vertebrate development and disease. AIM 1。揭示新型P120-Catenin的核功能：静止/Corest复合物。 AIM 2。揭示新型PKP3-Catenin：ETV1复合物的核功能。目标3。p120-，plakophilin3-和β-catenin核功能的全基因组分析。 β-catenin和人类疾病中的典型Wnt信号的关键性质牢固，但相反，其他同样在人类胚胎发生和疾病中起着关键作用的核贡献也相反。通过深入研究我们发现的两种新型链氨酸蛋白酶复合物的核作用（分别涉及P120-和PKP3-catenin），并在更广泛的整个基因组水平上揭示了这些Catenins的核角色，我们将对我们假设的catenin功能的首次理解是为了维持健康所需的综合网络。