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）：所提出的研究的长期目标是确定26S蛋白体介导的UMP在细胞命运决定过程中的作用，该作用已被证明在细胞命运决定中发挥着关键作用。虽然广泛参与早期胚胎发生过程中的细胞命运决定，但目前人们对 UMP 在背腹模式中的确切作用和调节知之甚少。先前的研究表明，这为胚层的生成和组织和器官的个体发育奠定了基础。来自背侧信号传导中心的-连环蛋白和来自腹侧信号传导中心的 Xom 受 UMP 控制，众所周知，在早期胚胎发生过程中，腹侧 (Xom) 信号传导拮抗背侧 (¿-连环蛋白) 信号传导，然而，UMP 的内在功能。背腹信号传导尚不清楚。该应用的目标是确定 UMP 在平衡背侧和腹侧信号中的功能。该研究源自主要研究者的初步研究，这使他能够进行研究。提出这样的假设：Xom 通过 GSK 介导的 ¿ 蛋白水解来拮抗背侧信号传导研究人员建议通过结合生化和遗传学方法以及非洲爪蟾模型，通过以下两个具体目标进一步检验他们的假设：确定 Xom 诱导的蛋白水解机制。 -catenin 体外通过定义 GSK3 激酶和 Ser33/37 磷酸化的参与此外，他们还将识别诱导 ¿ 蛋白水解所需的 Xom 关键结构域。 -连环蛋白 2 将定义 Xom 对 UMP 的影响 ¿ -catenin 在体内通过确定 Xom 和 GSK3 在 ¿ 的时间和空间表达模式中的影响早期胚胎发生过程中的连环蛋白和 mRNA 的研究结果将引入背腹不对称形成的新范式，并有望为了解干细胞功能和未来先天畸形和肿瘤疾病的治疗铺平道路。 。 项目叙述：控制背腹轴形成的分子机制代表了早期胚胎发生的一个基本挑战。拟议的研究将集中于泛素介导的蛋白水解在背腹模式形成中的作用。这些研究的结果将广泛涉及。预防先天畸形、调节干细胞功能以及治疗肿瘤疾病。