Modulators of Mad Family Function: MIx and mSin3A

Mad Family 功能的调制器：MIx 和 mSin3A

• 批准号: 7849473
• 负责人: Donald E Ayer
• 金额: $ 30.54万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849473
• 关键词: Affinity; Amino Acids; Bioenergetics; Cell Nucleus; Cells; Complex; Data; Diploidy; Disease; Enzymes; Family; Fibroblasts; Foundations; Gene Targeting; Glucose; Glucose-6-Phosphate; Glycolysis; Goals; Growth; Helix-Turn-Helix Motifs; Homeostasis; Human; In Vitro; Knowledge; Lead; Leucine Zippers; Maintenance; Malignant Neoplasms; Metabolic; Metastatic Lesion; Methods; Mitochondria; Modeling; Molecular; Nuclear; Nuclear Translocation; Nucleotides; Oncogene Proteins; Oncogenes; Oncogenic; Organelles; Outer Mitochondrial Membrane; Pathway interactions; Physiological; Proteins; Publishing; RNA Interference; Regulation; Research Personnel; Respiration; Role; Signal Pathway; Signal Transduction; Structure; Transcription Coactivator; Transcriptional Activation; Up-Regulation; c-myc Genes; gain of function; hexokinase; insight; lipid biosynthesis; meetings; member; metaplastic cell transformation; neoplastic cell; novel; programs; receptor; research study; response; therapeutic target; transcription factor; tumor; tumorigenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): A feature common to tumor cells is a high glycolytic rate. Increased glycolysis provides tumors with a selective growth advantage by supplying ATP to meet their high bioenergetic needs, and by supplying glucose-derived precursors required for nucleotide, amino acid and lipid biosynthesis. How tumor cells undergo the switch from respiration to glycolysis and the contribution of this switch to tumorigenesis is not fully understood. Elucidating the control mechanisms that underlie increased glycolysis in tumorigenesis will provide important insights into how misregulation of energy homeostasis contributes to cancer. Furthermore, understanding causative pathways in detail will provide additional therapeutic targets for the treatment of this devastating disease. We have discovered a new member of the basic helix-loop-helix leucine zipper family of transcription factors called MondoA. MondoA is related to the Myc proto-oncoprotein. Unlike Myc, which localizes to the nucleus, MondoA and its partner Mix localize to the outer mitochondrial membrane. Importantly, the mitochondrial localization of MondoA is not static; the protein shuttles between mitochondria and the nucleus. This shuttling suggests a role for MondoA in communicating information about intracellular bioenergetic state between these two essential organelles. Consistent with this hypothesis, when MondoA is expressed in the nucleus it upregulates glycolysis by direct transcriptional activation of rate-limiting glycolytic target genes. Further, MondoA is upregulated by oncogenic signaling pathways and regulates glycolysis in transformed diploid human fibroblasts, suggesting that it may drive the switch from respiration to glycolysis that accompanies, and is necessary for cellular transformation. We will determine the role of MondoA in regulating glycolysis and tumorigenesis in a genetically defined model of cellular transformation using loss - and gain-of-function experiments (Aim 1). We will determine how MondoA levels and glycolytic rate are dictated by upstream oncogenes such as Myc and Ras (Aim 2). We have discovered that the subcellular distribution of MondoA is controlled by a glucose-derived metabolite. In Aim 3, we will identify this metabolite and the mechanisms by which it controls the subcellular localization of MondoA. Finally, we will determine how MondoA interacts with mitochondria by identifying its mitochondrial receptor (Aim 4).

描述（由申请人提供）：肿瘤细胞的一个共同特征是高糖酵解率。糖酵解的增加通过提供ATP来满足肿瘤的高生物能量需求，并通过提供核苷酸、氨基酸和脂质生物合成所需的葡萄糖衍生前体，为肿瘤提供了选择性生长优势。肿瘤细胞如何经历从呼吸到糖酵解的转换，以及这种转换对肿瘤发生的贡献尚不完全清楚。阐明肿瘤发生中糖酵解增加的控制机制将为了解能量稳态失调如何导致癌症提供重要见解。此外，详细了解致病途径将为治疗这种毁灭性疾病提供额外的治疗靶点。我们发现了基本螺旋-环-螺旋亮氨酸拉链转录因子家族的一个新成员，叫做MondoA。MondoA与Myc原癌蛋白有关。与定位于细胞核的Myc不同，MondoA及其伙伴Mix定位于线粒体外膜。重要的是，MondoA的线粒体定位不是静态的；这种蛋白质穿梭于线粒体和细胞核之间。这种穿梭表明MondoA在这两个基本细胞器之间传递有关细胞内生物能量状态的信息。与这一假设一致，当MondoA在细胞核中表达时，它通过直接转录激活限速糖酵解靶基因来上调糖酵解。此外，MondoA在致癌信号通路中上调，并调节转化的二倍体人成纤维细胞中的糖酵解，这表明它可能驱动从呼吸到糖酵解的转变，这是细胞转化所必需的。我们将通过功能丧失和功能获得实验确定MondoA在调节糖酵解和肿瘤发生中的作用（目的1）。我们将确定MondoA水平和糖酵解速率是如何由上游癌基因如Myc和Ras决定的（目的2）。我们发现MondoA的亚细胞分布是由葡萄糖衍生的代谢物控制的。在Aim 3中，我们将鉴定这种代谢物及其控制MondoA亚细胞定位的机制。最后，我们将通过鉴定其线粒体受体来确定MondoA如何与线粒体相互作用（Aim 4）。