Regulation of TGF-beta Signaling and Embryonic Development by GTPases

GTPases 对 TGF-β 信号传导和胚胎发育的调节

基本信息

批准号：
7817175
负责人：
GERALD H THOMSEN
金额：
$ 28.64万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7817175
关键词：
Activins Affect Animal Cap Animals Antisense Oligonucleotides Binding Biochemical Biochemistry Biological Assay Biological Process Biology Blood Body Patterning Cancer Etiology Cell Death Cell Differentiation process Cell Shape Cell Survival Cell physiology Chromosomal translocation Clinical Treatment Congenital Abnormality Cultured Cells Data Development Disease Drug Delivery Systems Elongation Factor Embryo Embryo Loss Embryonic Development Fibrosis GTP Binding Gene Activation Genes Genetic Transcription Glioblastoma Goals Grant Guanine Nucleotides Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heart Hypertension Link Malignant neoplasm of brain Mammalian Cell Mediating Mesoderm Mitosis Molecular Molecular Weight Monomeric GTP-Binding Proteins Nervous system structure Nodal Organ Organogenesis Pathway interactions Pattern Phenotype Process Proteins Regulation Reporter Genes Role Signal Transduction Signaling Protein Smad Proteins Smad protein Somites Specificity Staging Surveys Tadpoles Testing Tissues Transducers Transforming Growth Factor beta Transforming Growth Factors Translating Translations Xenopus base blastomere structure cell growth cell motility egg embryonic cell culture loss of function receptor response xenopus development

项目摘要

DESCRIPTION (provided by applicant): GTPases govern critical cellular processes such as signal transduction, transcription, mitosis, cell shape and cell movement by acting as molecular switches that regulate activity of protein partners. The functions of small GTPases such as Ras and RhoA are relatively well understood, but there exists a variety of large molecular weight GTPases whose functions are poorly characterized. GTPBP1 and GTPBP2 are unique, large GTPases, distantly related to translation elongation factor EF1-alpha. Their biochemical and biological functions, however, are completely unknown. We have made a breakthrough by discovering that GTPBP1 and GTPBP2 interact with Smad proteins, the principal signal transducers for the Transforming Growth Factor-¿, (TGF¿) superfamily. GTPBP2 in particular enhances signaling by the BMP and nodal/activin branches of TGF¿ signaling in embryo and cultured cell assays. The GTPBP genes are expressed during early Xenopus embryogenesis and during subsequent organogenesis of somites, blood, heart and nervous system. Blocking endogenous GTPBP 1 or 2 in developing embryos with antisense oligonucleotides disrupts mesoderm differentiation, body patterning and organogenesis. In this grant, we propose to investigate how GTPBP 1 and 2 regulate TGF¿ signaling and early vertebrate development. Aim 1 will define the specificity and molecular basis of interaction between GTPBPs and Smads. Aim 2 will investigate how GTPBPs influence BMP and nodal/activin signaling, using differentiation and reporter gene assays. Aim 3 will investigate the developmental roles of the GTPBPs in Xenopus embryos by gain and loss of function, and we will begin a search for links between GTPBPs and upstream pathways. The TGF¿ superfamily controls cell growth, cell death, differentiation and development, and abnormal TGF¿ signaling causes cancer, hypertension, fibroses and other diseases and birth defects. Likewise, abnormalities in GTPases cause cancer, a wide range of diseases, and birth defects. Thus, TGF¿ signaling proteins and GTPases are popular drug targets. Whether dysfunctional GTPBP1/2 affect disease is not known, but a chromosomal translocation of GTPBP2 has recently been identified in glioblastoma, a nearly incurable brain cancer. Our studies will provide crucial information about GTPBPs which may eventually translate into clinical treatments for diseases caused by abnormal TGF¿ or GTPBP signaling.

描述（由申请人提供）：GTP酶通过充当调节蛋白质伴侣活性的分子开关来控制关键的细胞过程，例如信号转导、转录、有丝分裂、细胞形状和细胞运动。Ras和RhoA等小GTP酶的功能相对较弱。众所周知，但存在多种大分子量 GTP 酶，其功能尚不清楚。 GTPBP1 和 GTPBP2 是独特的大 GTP 酶，与翻译延伸因子关系较远。然而，它们的生化和生物学功能完全未知，我们通过发现 GTPBP1 和 GTPBP2 与 Smad 蛋白（转化生长因子的主要信号转导器）相互作用而取得了突破。 , (TGF¿) GTPBP2 特别增强 TGF¿ 的 BMP 和节点/激活素分支的信号传导。 GTPBP 基因在非洲爪蟾早期胚胎发生过程中以及随后的体节、血液、心脏和神经系统的器官发生过程中表达，用反义寡核苷酸阻断发育中的胚胎中的内源性 GTPBP 1 或 2 会破坏中胚层分化、身体模式和发育。在这笔资助中，我们建议研究 GTPBP 1 和 2 如何调节 TGF¿目标 1 将定义 GTPBP 和 Smad 之间相互作用的特异性和分子基础，目标 2 将使用分化和报告基因分析研究 GTPBP 如何影响 BMP 和节点/激活素信号。爪蟾胚胎中 GTPBP 的功能获得和丧失，我们将开始寻找 GTPBP 与上游途径之间的联系。超家族控制细胞生长、细胞死亡、分化和发育以及异常 TGF¿同样，GTP酶的异常会导致癌症、多种疾病和出生缺陷。信号蛋白和 GTP 酶是流行的药物靶标。功能失调的 GTPBP1/2 是否会影响疾病尚不清楚，但最近在胶质母细胞瘤（一种几乎无法治愈的脑癌）中发现了 GTPBP2 的染色体易位，我们的研究将提供有关 GTPBP 的重要信息。转化为针对异常TGF引起的疾病的临床治疗¿或 GTPBP 信号传导。