MAD SIGNAL TRANSDUCTION MOLECULES IN XENOPUS DEVELOPMENT

我的研究项目的主要目标是了解 在TGFbeta家族中调节胚胎发育 非洲爪哇两栖动物。利用非洲爪哇和其他动物进行研究 两栖动物为理解 脊椎动物的发育和调节细胞的机制 差异化。在脊椎动物胚胎中，激活素、Vg1、Node和BMP 中胚层的诱导和图案化涉及的因素 纸巾。在非洲爪哇，激活素、Vg1和节蛋白诱导背部 中胚层，如头部组织、脊索(胚胎的脊椎) 和肌肉，而骨形态发生蛋白诱导弯曲的中胚层，如血液。过去时 首席调查员的努力有助于 对非洲爪哇激活素、Vg1和BMPs功能的认识 发展。 这项拟议的研究将使用非洲爪哇来研究胚胎 MAD蛋白家族中信号转导分子的功能， 它们传递来自TGFβ生长因子受体的信号。几个 已经在脊椎中发现了与MAD相关的基因，其中， MAD1和MAD2已被证明在发育过程中起作用 非洲爪哇的胚胎。MAD1信号转导来自BMP受体和 MAD2通过激活素受体或激活素受体传递信号 具有激活素样效应的因子，如Vg1和Node。MAD蛋白质 也代表了一类新的肿瘤抑制基因：突变 MAD2DPC4分别与结肠癌和胰腺肿瘤有关。 MADs是癌症治疗干预的潜在靶点。我们的 因此，拟议的对MAD蛋白质的检查将提供基本的 关于转化生长因子β信号转导机制的信息， 脊椎动物胚胎发生和癌症发生。 实验将调查几个主题：(A)空间和 MAD1和MAD2蛋白的时间表达将被检测 在胚胎发育过程中，以及它们的行为(例如，化学物质 修饰、亚细胞分布)以响应转化生长因子β生长 这些因素将受到监控。(B)MAD1和MAD2将被诱变 并在胚胎中进行检测，以确定蛋白质结构域和关键氨基酸 负责他们特定的生物活动和 对转化生长因子β家族受体的生化反应。(C)A类 将在酵母中进行遗传筛选，以分离相互作用的蛋白质 具有MAD1和MAD2，并且可能用作其他组件 在转化生长因子β信号转导通路中。

The broad goal of my research program is to understand how factors in the TGFbeta family regulate embryonic development in the amphibian Xenopus laevis. Studies using Xenopus and other amphibians have made seminal contributions to the understanding of vertebrate development and mechanisms that regulate cell differentiation. In vertebrate embryos activin, Vg1, nodal and BMP factors are involved in the induction and patterning of mesodermal tissues. In Xenopus, activin, Vg1 and nodal proteins induce dorsal mesoderm, such as head tissues, notochord (the embryonic backbone) and muscle, while BMPs induce bentral mesoderm such as blood. Past efforts of the principal investigator have contributed to the understanding of the function of activin, Vg1 and BMPs in Xenopus development. The proposed research will use Xenopus to investigate the embryonic function of signal transduction molecules in the MAD protein family, which convey signals from TGFbeta growth factor receptors. Several MAD-related genes have been identified in vertebraes, and of these, MAD1 and MAD2 have been shown to function in the development of Xenopus embryos. MAD1 transduces signals from BMP receptors and MAD2 transduces signals from activin receptors, or receptors for factors with activin-like effects, such as Vg1 and nodal. MAD proteins also represent a new class of tumor suppressor genes: mutations in MAD2 DPC4 contribute to colon and pancreatic tumors, respectively. MADs are potential targets for therapeutic intervention in cancer. Our proposed examination on MAD proteins will thus provide fundamental information about the mechanisms of TGFbeta signal transduction, vertebrate embryogenesis, and carcinogenesis. Experiments will investigate several topics: (a) The spatial and temporal expression of MAD1 and MAD2 proteins will be examined over the course of embryogenesis, and their behavior (e.g. chemical modification, subcellular distribution) in response to TGFbeta growth factors will be monitored. (B) MAD1 and MAD2 will be mutagenized and assayed in embryos to define protein domains and key amino acids that are responsible for their particular biological activitites and biochemical responses to receptors in the TGFbeta family. (C) A genetic screen in yeast wil be performed to isolate proteins that interact with MAD1 and MAD2 and potentially function as other components in TGFbeta signal transduction pathways.