Ras/ERK control of cell fates

Ras/ERK 控制细胞命运

• 批准号: 7464421
• 负责人: Meera Sundaram
• 金额: $ 31.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464421
• 关键词: Address; Affect; Animal Model; Animals; Binding; Biological; Biological Assay; Bromodomain; CCL4 gene; Caenorhabditis elegans; Cell Fate Control; Cells; DNA Binding; Development; Disease; Duct (organ) structure; Gene Expression; Genes; Genetic; Homeodomain Proteins; Human; Kidney; MEKs; Malignant Neoplasms; Mediating; Modeling; Nuclear; Outcome; Phenotype; Phosphotransferases; Process; Protein Family; Proteins; RNA Interference; Regulation; Regulator Genes; Relative (related person); Role; Screening procedure; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; Syndrome; System; Testing; Tissues; Up-Regulation; Vulva; Zinc Fingers; base; cell type; cofactor; in vivo; member; mutant; nephrogenesis; novel; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): The Ras-stimulated Raf-MEK-ERK kinase cascade is used over and over again to control many aspects of normal, and abnormal, animal development. How this common signaling cascade elicits specific responses is still poorly understood. ERK is thought to phosphorylate multiple targets that may differ among cell types and that act combinatorially with ERK-independent factors to elicit the appropriate response. However, the relative importance of different ERK targets in vivo and how ERK chooses targets appropriate for a given tissue or circumstance is still poorly understood, as are the more downstream gene regulatory networks that ultimately control cellular responses. We are studying this problem in the simple model organism C. elegans, where Ras-ERK specifies the fates of the excretory duct, P12 ectoblast, vulva and other tissues. One "general" target of ERK in all three tissues is the Elk1-related Ets transcription factor LIN-1. We've discovered two other potential general targets, the BTB/Zinc finger protein EOR-1 and the novel (but conserved) protein EOR-2. In Aim 1 we will use a combination of protein interaction studies, worm genetics and DNA binding assays to determine how EOR-1 and EOR-2 cooperate with LIN-1 to control downstream responses to Ras/ERK. In Aim 2 we will focus on how Ras/ERK promotes one specific cell fate, that of the excretory duct, an essential component of the worm's primitive renal system. We will test the roles of two candidate duct-specific Ras-ERK targets, an Nkx5/Hmx-family homeodomain protein and a conserved bromodomain protein, to understand how they promote tissue-appropriate responses to Ras-ERK. Finally we will continue our RNAi-based screens to identify additional genes that are important for the excretory duct fate. These studies will help to answer the question of how the commonly used Ras-ERK signaling pathway elicits different biological responses in different cell types. All of the candidate ERK targets we'll study are conserved in humans. Since several proteins we'll study are causative agents in human cancers, these studies may suggest strategies for treating those cancers. The control of excretory duct cell development also may be a simple model relevant for understanding kidney development and malfunction in humans. Public Health Relevance: These studies will help to answer the question of how a commonly used signaling pathway elicits different biological responses in different cell types. Since several proteins we'll study are causative agents in human cancers and developmental syndromes, these studies may suggest strategies for treating those disorders.

描述（由申请人提供）：Ras 刺激的 Raf-MEK-ERK 激酶级联被反复使用来控制正常和异常动物发育的许多方面。这种常见的信号级联如何引发特定反应仍知之甚少。 ERK 被认为可以磷酸化多个靶标，这些靶标可能因细胞类型而异，并且与 ERK 独立因子联合作用以引发适当的反应。然而，体内不同 ERK 靶点的相对重要性以及 ERK 如何选择适合特定组织或环境的靶点仍然知之甚少，最终控制细胞反应的下游基因调控网络也是如此。我们正在简单的模型生物秀丽隐杆线虫中研究这个问题，其中 Ras-ERK 指定排泄管、P12 外胚层、外阴和其他组织的命运。 ERK 在所有三种组织中的一个“通用”靶标是 Elk1 相关的 Ets 转录因子 LIN-1。我们还发现了另外两个潜在的通用靶标，BTB/锌指蛋白 EOR-1 和新型（但保守）蛋白 EOR-2。在目标 1 中，我们将结合蛋白质相互作用研究、蠕虫遗传学和 DNA 结合测定来确定 EOR-1 和 EOR-2 如何与 LIN-1 配合来控制 Ras/ERK 的下游反应。在目标 2 中，我们将重点关注 Ras/ERK 如何促进一种特定的细胞命运，即排泄管的命运，排泄管是蠕虫原始肾系统的重要组成部分。我们将测试两个候选导管特异性 Ras-ERK 靶标（Nkx5/Hmx 家族同源结构域蛋白和保守的溴结构域蛋白）的作用，以了解它们如何促进对 Ras-ERK 的组织适当反应。最后，我们将继续基于 RNAi 的筛选，以确定对排泄管命运重要的其他基因。这些研究将有助于回答常用的Ras-ERK信号通路如何在不同细胞类型中引发不同生物反应的问题。我们将研究的所有候选 ERK 靶点在人类中都是保守的。由于我们将研究的几种蛋白质是人类癌症的致病因子，因此这些研究可能会提出治疗这些癌症的策略。排泄管细胞发育的控制也可能是与理解人类肾脏发育和功能障碍相关的简单模型。 Public Health Relevance: These studies will help to answer the question of how a commonly used signaling pathway elicits different biological responses in different cell types.由于我们将研究的几种蛋白质是人类癌症和发育综合征的致病因子，因此这些研究可能会提出治疗这些疾病的策略。