Regulation of beta-catenin proteolysis in dorsal-ventral patterning

背腹模式中β-连环蛋白水解的调节

• 批准号: 8113749
• 负责人: ZHENGLUN ZHU
• 金额: $ 8.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113749
• 关键词: 26S proteasome; Biochemical Genetics; Cell physiology; Cells; Complex; Congenital Abnormality; Data; Disease; Dorsal; Embryo; Embryonic Development; Equilibrium; Foundations; Future; Generations; Germ Layers; Goals; In Vitro; Investigation; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; Methods; Modeling; Molecular; Organ; Pattern; Pattern Formation; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Proteins; Proteolysis; Regulation; Research; Research Personnel; Role; Signal Transduction; Stem cells; Testing; Tissues; Ubiquitin-mediated Proteolysis Pathway; Work; Xenopus; base; beta catenin; in vivo; insight; loss of function; mutant; neoplastic; novel; prevent; research study; tissue regeneration

DESCRIPTION (Provided by Applicant): The long-term goal of the proposed studies is to define the role of ubiquitin-mediated proteolysis (UMP) in cell fate determination during dorsoventral patterning. UMP by the 26S proteosome has been shown to play critical roles in regulating cellular activities. While broadly implicated in cell fate determination during early embryogenesis, currently little is known about the exact role and regulation of UMP in dorsoventral patterning, which forms the foundation for the generation of germ layers and ontogenesis of tissues and organs. Previous studies have shown that both ¿-catenin from the dorsal signaling center and Xom from the ventral signaling center are controlled by UMP. It is well appreciated that during early embryogenesis, ventral (Xom) signaling antagonizes dorsal (¿-catenin) signaling; nevertheless, the intrinsic function of UMP in dorsoventral signaling is not clear. The goal of this application is to define the function of UMP in balancing dorsal and ventral signals. The research derives from the principal investigator's preliminary studies, which allowed him to formulate the hypothesis that Xom antagonizes dorsal signaling through GSK-mediated proteolysis of ¿-catenin. Using combined biochemical and genetic approaches and a Xenopus model, the investigators propose to further test their hypothesis through the following two specific aims. Aim 1 will determine the mechanisms of Xom-induced proteolysis of ¿-catenin in vitro by defining the involvement of GSK3 kinase and Ser33/37 phosphorylation. In addition they will identify the critical domain of Xom required for inducing proteolysis of ¿-catenin. Aim 2 will define the effects of Xom on UMP of ¿-catenin in vivo by determining the effects of Xom and GSK3 in the temporal and spatial expression pattern of the ¿-catenin protein and mRNA during early embryogenesis. The results of the proposed studies will introduce a new paradigm underlying the formation of dorsal-ventral asymmetry, and are expected to pave the way for understanding stem cell function and future management of congenital malformations and neoplastic diseases. PROJECT NARRATIVE: Molecular mechanisms controlling the formation of dorsal-ventral axis formation represent a fundamental challenge of early embryogenesis. The proposed studies will focus on the role of ubiquitin-mediated proteolysis in dorsoventral patterning formation. The results of these studies will be broadly implicated in preventing congenital malformation, regulating stem cell function, as well as managing neoplastic diseases.

描述（由申请人提供）：拟议的研究的长期目标是定义泛素介导的蛋白水解（UMP）在背腹图期间细胞脂肪测定中的作用。 26S蛋白体的UMP已显示在调节的细胞活性中起关键作用。虽然在早期胚胎发生过程中广泛实施了细胞脂肪的确定，但目前对UMP在背腹图案中的确切作用和调节知之甚少，后腹形成型，这构成了生成细菌层和组织和器官的成生的基础。先前的研究表明，背面信号中心的 - 帕宁蛋白和腹侧信号中心的XOM均由UMP控制。人们非常理解的是，在早期胚胎发生期间，腹侧（XOM）信号传导拮抗背（-Catenin）信号传导。然而，背腹信号传导中UMP的固有功能尚不清楚。该应用的目的是定义UMP在平衡背和腹侧信号中的功能。该研究源自主要研究者的初步研究，这使他能够通过GSK介导的 - catenin的蛋白水解来提出XOM拮抗背信号传导的假设。研究人员使用合并的生化和遗传方法以及爪蟾模型，建议通过以下两个特定目标进一步检验其假设。 AIM 1将通过定义GSK3激酶和SER33/37磷酸化的参与来确定XOM诱导的 - 蛋白水解的机制。另外，它们将确定诱导» - 蛋白质水解所需的XOM的关键结构域。 AIM 2将通过确定XOM和GSK3在早期胚胎发生过程中xom和gsk3对 - xom和gsk3的影响来定义XOM对体内 - 帕宁蛋白在体内UMP的影响。拟议研究的结果将引入一个新的范式，该范式是背腹不对称的形成，并有望为理解干细胞功能以及先天性畸形和肿瘤疾病的未来管理铺平道路。 项目叙述：控制背腹轴形成形成的分子机制代表了早期胚胎发生的基本挑战。拟议的研究将重点介绍泛素介导的蛋白水解在背腹形成形成中的作用。这些研究的结果将广泛涉及预防先天性畸形，调节干细胞功能以及管理肿瘤疾病。