Modulators of Mad Family Function: MIx and mSin3A

描述（由申请人提供）：肿瘤细胞的一个共同特征是高糖酵解速率。糖酵解增加通过提供ATP以满足其高生物能量需求，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未完全了解。阐明肿瘤发生中糖酵解增加的控制机制将为能量稳态失调如何导致癌症提供重要的见解。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。我们已经发现了一个新成员的基本螺旋环螺旋亮氨酸拉链家族的转录因子称为MondoA。MondoA与Myc原癌蛋白相关。与Myc定位于细胞核不同，MondoA及其伴侣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;该蛋白在线粒体和细胞核之间穿梭。这种穿梭表明MondoA在这两个基本细胞器之间传递细胞内生物能量状态信息中的作用。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通过致癌信号传导途径上调，并调节转化的二倍体人成纤维细胞中的糖酵解，这表明它可能驱动伴随的从呼吸到糖酵解的转换，并且是细胞转化所必需的。我们将确定MondoA在调节糖酵解和肿瘤发生中的作用，在遗传定义的细胞转化模型中使用功能丧失和获得实验（目的1）。我们将确定MondoA水平和糖酵解速率如何由上游癌基因如Myc和Ras决定（Aim 2）。我们已经发现MondoA的亚细胞分布受葡萄糖衍生的代谢产物控制。在目标3中，我们将确定这种代谢产物及其控制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）。

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).