Control of Metabolism and Energy-Sensing Pathways by c-Myc

c-Myc 对代谢和能量传感途径的控制

• 批准号: 8876612
• 负责人: Edward Victor Prochownik
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876612
• 关键词: Acetylation; Affect; Area; Biogenesis; Biology; Cell Proliferation; Cells; Citric Acid Cycle; Complement; Complex; Deacetylase; Electron Transport; Energy Metabolism; Energy Supply; Equilibrium; Family member; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Glycolysis; Glycolysis Pathway; Health; Human; In Vitro; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic Control; Metabolism; Methodology; Mitochondria; Mitochondrial Proteins; Monitor; Oncogene Proteins; Pathway interactions; Phenotype; Process; Production; Protein Acetylation; Protein Kinase; Proteins; Regulation; Research Personnel; Role; Signal Pathway; Sirtuins; Structure; Up-Regulation; Warburg Effect; ZIP protein; aerobic glycolysis; base; c-myc Genes; cell transformation; energy balance; fatty acid metabolism; in vivo; in vivo Model; lipid biosynthesis; meetings; protein function; rapid growth; reconstitution; response; sensor; transcription factor; tumor

DESCRIPTION (provided by applicant): T Malignant transformation is associated with numerous phenotypic alterations, some of which promote proliferation. Many of the signaling pathways involved in these changes ultimately converge upon the c- Myc (Myc) oncoprotein, a bHLH-ZIP transcription factor with hundreds of genetic targets. Indeed, primary de-regulation of Myc itself occurs in many cancers. The rapid growth and proliferation of Myc-transformed cells is associated with the up-regulation of anabolic pathways which supply the macromolecular precursors necessary to maintain these activities. It is currently believed that Myc alters metabolism by diverting glycolytic and TCA cycle intermediates into these anabolic pathways while concurrently increasing ATP synthetic rates to meet increased cellular energy demands. This may partly explain why many tumors display aerobic glycolysis (The Warburg Effect). We have recently shown that Myc is also needed to maintain the structure and function of mitochondrial electron transport chain (ETC) Complexes I and V, thus explaining why Myc-deficient cells are severely ATP-depleted. In extension of these findings, we have also observed that Myc regulates mitochondrial protein function at the post-translational level through its up-regulation of sirtuin 3 (Sirt3), the major mitochondrial protein deacetylase. Therefore, in Specifi Aim 1, we propose to determine how Sirt3 and Myc cooperatively regulate mitochondrial structure and function by determining how the major protein targets of Sirt3 are altered by Myc and acetylation. We also provide evidence that, in response to Myc inactivation and ATP depletion, the energy-sensing AMP-dependent protein kinase (AMPK) is activated to dampen energy-utilizing anabolic processes and restore ATP levels. Therefore, in Specific Aim 2, we will determine how Myc and AMPK communicate to balance metabolism and ATP levels. Finally, we provide evidence that Myc and the related Myc family member bHLH-ZIP protein, ChREBP, also communicate by coordinately regulating an as yet incompletely defined repertoire of glycolytic and lipogenic genes and that ChREBP expression as a pro-anabolic factor is inversely correlated with that of anti-anabolic AMPK. Therefore, Specific Aim 3 will characterize Myc's and ChREBP's cooperating roles in energy-generating processes particularly those related to glycolysis and lipogenesis. The overriding hypothesis of this application is that Myc communicates with and regulates energy sensing pathways, glycolysis, lipogenesis and the direct and post-translational control of mitochondrial function as a means of controlling cell proliferation. The proposed studies will utilize state-of-the-art methodologies and complementing in vitro and in vivo models. The three co-investigators possess strong and synergistic collaborative ties as well as specific areas of expertise in Myc biology (Prochownik), mitochondrial sirtuins and fatty acid metabolism (Goetzman), and glycolytic and lipogenic gene regulation (Scott).

描述（由申请人提供）：T恶性转化与许多表型改变相关，其中一些促进增殖。参与这些变化的许多信号传导途径最终会聚在c-Myc（Myc）癌蛋白上，这是一种具有数百个遗传靶标的bHLH-ZIP转录因子。事实上，Myc本身的原发性失调发生在许多癌症中。Myc转化细胞的快速生长和增殖与合成代谢途径的上调有关，合成代谢途径提供维持这些活性所需的大分子前体。目前认为，Myc通过将糖酵解和TCA循环中间体转移到这些合成代谢途径中来改变代谢，同时增加ATP合成速率以满足增加的细胞能量需求。这可以部分解释为什么许多肿瘤显示有氧糖酵解（瓦尔堡效应）。我们最近发现，Myc也需要维持线粒体电子传递链（ETC）复合物I和V的结构和功能，从而解释了为什么Myc缺陷细胞ATP严重耗尽。在这些发现的扩展中，我们还观察到Myc通过上调sirtuin 3（Sirt 3）（主要的线粒体蛋白脱乙酰酶）在翻译后水平调节线粒体蛋白质功能。因此，在Specifi Aim 1中，我们提出通过确定Sirt 3的主要蛋白靶点如何被Myc和乙酰化改变来确定Sirt 3和Myc如何协同调节线粒体结构和功能。我们还提供了证据表明，在响应Myc失活和ATP耗竭，能量敏感AMP依赖性蛋白激酶（AMPK）被激活，以抑制能量利用合成代谢过程和恢复ATP水平。因此，在具体目标2中，我们将确定Myc和AMPK如何沟通以平衡代谢和ATP水平。最后，我们提供的证据表明，Myc和相关的Myc家族成员bHLH-ZIP蛋白，ChREBP，也通过协调调节糖酵解和脂肪生成基因的一个尚未完全定义的库，ChREBP表达作为促合成代谢因子与抗合成代谢AMPK呈负相关。因此，特定目标3将表征Myc和ChREBP在能量产生过程中的合作作用，特别是与糖酵解和脂肪生成相关的过程。本申请的首要假设是Myc与能量传感途径、糖酵解、脂肪生成和线粒体功能的直接和翻译后控制通信并调节能量传感途径、糖酵解、脂肪生成和线粒体功能的直接和翻译后控制作为控制细胞增殖的手段。拟议的研究将利用最先进的方法，并补充体外和体内模型。这三位共同研究者拥有强大的协同合作关系，以及Myc生物学（Prochownik），线粒体sirtuins和脂肪酸代谢（Goetzman）以及糖酵解和脂肪生成基因调控（Scott）的特定专业领域。