Modulators of Mad Family Function: MIx and mSin3A

Mad Family 功能的调制器：MIx 和 mSin3A

• 批准号: 7911391
• 负责人: Donald E Ayer
• 金额: $ 26.44万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911391
• 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。糖酵解的增加为肿瘤提供了选择性生长优势，通过提供 ATP 来满足其高生物能需求，并提供核苷酸、氨基酸和脂质生物合成所需的葡萄糖衍生前体。肿瘤细胞如何经历从呼吸到糖酵解的转变以及这种转变对肿瘤发生的贡献尚不完全清楚。阐明肿瘤发生过程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破坏性疾病提供额外的治疗靶点。我们发现了转录因子基本螺旋-环-螺旋亮氨酸拉链家族的一个新成员，称为 MondoA。 MondoA 与 Myc 原癌蛋白相关。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。蛋白质在线粒体和细胞核之间穿梭。这种穿梭表明 MondoA 在这两个重要细胞器之间传递细胞内生物能状态信息方面发挥着作用。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 受到致癌信号通路的上调，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伴随的糖酵解的转变，并且是细胞转化所必需的。我们将使用功能丧失和获得功能实验来确定 MondoA 在基因定义的细胞转化模型中调节糖酵解和肿瘤发生中的作用（目标 1）。我们将确定 MondoA 水平和糖酵解速率如何由上游癌基因（例如 Myc 和 Ras）决定（目标 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。在目标 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，我们将通过识别 MondoA 的线粒体受体来确定 MondoA 如何与线粒体相互作用（目标 4）。