Glucose Signaling in Plants

描述（由申请人提供）：葡萄糖是一种古老的和中央的信号分子在广泛的生物体从大肠杆菌。大肠杆菌、酵母菌对植物和人类的影响。尽管葡萄糖在基因表达、生理学、代谢、细胞增殖和死亡、生长和发育以及人类疾病中起着重要作用，但葡萄糖信号传导的分子和细胞机制在植物和动物中仍然是难以捉摸的。我们在模式植物拟南芥中的研究提供了令人信服的遗传和生化证据，证明己糖激酶1（HXK 1）是一种进化上保守的葡萄糖传感器，它整合了营养和激素信号，以控制基因表达和植物生长对环境信号的响应。代谢酶如何介导葡萄糖信号仍然是一个谜。我们最近的研究结果表明，拟南芥HXK 1介导的葡萄糖信号转导没有其代谢活性，并与两个HXK 1非常规的合作伙伴（HUP 1：一个支架蛋白与HXK 1，HUP 2和转录因子（TF）相互作用; HUP 2：一个ATP酶与HXK 1，HUP 1和其他ATP酶相互作用）在细胞核中相互作用，以控制转录和不同的葡萄糖反应。本研究的目的是阐明拟南芥核传感器HXK 1调控葡萄糖信号转导的机制。拟议的实验旨在使用分子，细胞，遗传和基因组的方法来阐明HXK 1的功能和调节，并分析两套信号调节剂的核HXK 1-HUP 1/2复合物的下游作用。该项目将专注于使用转基因植物和葡萄糖传感器HXK 1，HXK 1信号伴侣HUP 1，新型转录因子（MYB，SCL 3，ZFP）和ATP酶（HUP 2/RPT 5，RPT 2和RPT 6）中具有特定缺陷的功能缺失突变体来表征和整合8个拟南芥基因在葡萄糖信号传导中的功能。近全基因组微阵列和染色质免疫沉淀（ChIP）将进行识别的主要HXK 1靶基因，并在体内表征其调控。该项目挑战了植物和动物中基于代谢的葡萄糖反应的现有范式，旨在建立一个新的概念框架，以提高我们对从植物到人类的葡萄糖信号传导的分子和细胞机制的理解。三个具体目标是：目标1。阐明核葡萄糖传感器HXK 1 Aim 2的功能和调控。表征HXK 1-HUP 1/2介导的葡萄糖信号传导中的三种新型TF。定义核RPT 5/2/6复合体中三种ATP酶的功能。公共卫生相关性：尽管葡萄糖在基因表达、生理学、代谢、细胞增殖和死亡、生长和发育以及人类疾病中起着中心作用，但葡萄糖信号传导的分子机制在植物和动物中仍然是难以捉摸的。我们最近的研究提供了令人信服的证据表明，葡萄糖信号可以从多细胞真核生物的葡萄糖代谢中解偶联，拟南芥己糖激酶1作为一个进化上保守的传感器在核葡萄糖信号中发挥关键作用。该研究将发现新的调节剂并阐明其在核葡萄糖信号传导中的功能，并为未来改善农业，环境和可再生能源生产以及人类健康提供创新工具，以治疗糖尿病，肥胖，癌症和葡萄糖信号传导调节的衰老。

DESCRIPTION (provided by applicant): Glucose is an ancient and central signaling molecule in a broad range of organisms from E. coli, yeast to plants and humans. Despite the essential roles of glucose in gene expression, physiology, metabolism, cell proliferation and death, growth and development, and human diseases, the molecular and cellular mechanisms of glucose signaling remain mostly elusive in plants and animals. Our research in the model plant Arabidopsis thaliana has provided compelling genetic and biochemical evidence that hexokinase1 (HXK1) is an evolutionarily conserved glucose sensor that integrates nutrient and hormone signals to govern gene expression and plant growth in response to environmental cues. How the metabolic enzyme mediates glucose signaling remains a mystery. Our recent findings indicate that Arabidopsis HXK1 mediates glucose signaling without its metabolic activity, and interacts with two HXK1 Unconventional Partners (HUP1: a scaffolding protein interacting with HXK1, HUP2 and transcription factors (TFs); HUP2: an ATPase interacting with HXK1, HUP1 and other ATPases) in the nucleus to control transcription and diverse glucose responses. The goal of this research project is to elucidate the mechanisms of glucose signaling controlled by the nuclear sensor HXK1 in Arabidopsis. The proposed experiments aim to use molecular, cellular, genetic, and genomic approaches to elucidate HXK1 functions and regulation, and to analyze two sets of signaling regulators acting downstream of the nuclear HXK1-HUP1/2 complex. The project will focus on characterizing and integrating functions of eight Arabidopsis genes in glucose signaling using transgenic plants and loss-of-function mutants with specific defects in the glucose sensor HXK1, HXK1 signaling partners HUP1, novel transcription factors (MYB, SCL3, ZFP) and ATPases (HUP2/RPT5, RPT2 and RPT6). Near whole-genome microarray and chromatin-immunoprecipitation (ChIP) will be carried out to identify the primary HXK1 target genes and characterize their regulation in vivo. The project challenges the existing paradigm on metabolism-based glucose responses in plants and animals, and aims to build a new conceptual framework to enhance our understanding of the molecular and cellular mechanisms of glucose signaling from plants to humans. Three Specific Aims are: Aim 1. Elucidate the functions and regulation of the nuclear glucose sensor HXK1 Aim 2. Characterize three novel TFs in HXK1-HUP1/2-mediated glucose signaling Aim 3. Define functions of three ATPases in the nuclear RPT5/2/6 complex. PUBLIC HEALTH RELEVANCE: In spite the central roles of glucose in gene expression, physiology, metabolism, cell proliferation and death, growth and development, and human diseases, the molecular mechanisms of glucose signaling remain elusive in plants and animals. Our recent research has provided compelling evidence that glucose signaling can be uncoupled from glucose metabolism in multicellular eukaryotes, and Arabidopsis hexokinase1 acts as an evolutionarily conserved sensor playing a pivotal role in nuclear glucose signaling. The proposed research will discover novel regulators and elucidate their functions in nuclear glucose signaling, and provide innovative tools for future improvement of agriculture, environment and renewable energy production, as well as human health in treating diabetes, obesity, cancer and ageing modulated by glucose signaling.