MAD SIGNAL TRANSDUCTION MOLECULES IN XENOPUS DEVELOPMENT

我的研究项目的主要目标是了解 在TGF β家族中调节胚胎发育 两栖动物非洲爪蟾 使用非洲爪蟾和其他 两栖动物对理解 脊椎动物的发育和调节细胞的机制 分化 在脊椎动物胚胎中，激活素、Vg1、nodal和BMP 因子参与中胚层的诱导和形成 组织中 在非洲爪蟾中，激活素、Vg 1和nodal蛋白诱导背侧 中胚层，如头部组织、脊索（胚胎的脊柱） 而BMP诱导的是血液等中胚层。 过去 主要研究者的努力有助于 了解非洲爪蟾中激活素、Vg 1和BMP的功能 发展 这项拟议中的研究将使用非洲爪蟾来研究胚胎 MAD蛋白家族中信号转导分子的功能， 其传递来自TGF β生长因子受体的信号。 几 已在脊椎动物中发现了与mad相关的基因，其中， MAD1和MAD2已被证明在以下发育中起作用： 非洲爪蟾胚胎 MAD1转导来自BMP受体的信号， MAD2从激活素受体或激活素受体转导信号。 具有激活素样效应的因子，如Vg1和nodal。 MAD蛋白 也代表了一类新的肿瘤抑制基因： MAD 2 DPC 4分别促进结肠和胰腺肿瘤。 MAD是癌症治疗干预的潜在靶点。 我们 因此，对MAD蛋白的拟议检查将提供基础知识 关于TGF β信号转导机制的信息， 脊椎动物胚胎发生和癌症发生。 实验将探讨几个主题：（a）空间和 将检测MAD1和MAD2蛋白的时间表达 在胚胎发生过程中，它们的行为（例如化学 修饰，亚细胞分布）对TGF β生长的反应 将对这些因素进行监测。 (B)将对MAD 1和MAD 2进行诱变 并在胚胎中进行分析以确定蛋白质结构域和关键氨基酸 负责其特定的生物活动， 对TGF β家族中的受体的生化反应。 (C)一 将在酵母中进行遗传筛选以分离相互作用的蛋白质 具有MAD 1和MAD 2，并可能用作其他组件 TGF β信号转导通路。

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.