Project 2 - PCG-1 Signaling and Mitochondrial Stress in Melanoma

总结-项目2：黑色素瘤中的PGC-1信号传导和线粒体应激 在黑色素瘤的形成、发展和治疗过程中，代谢发生了巨大的变化 并且是快速增殖细胞的进化能量和生物合成需要所必需的。线粒体 作为这种代谢重新编程的中心整合点;调节ATP合成能力，氧化还原 信号和生物合成能力。本P01应用程序中提供的初步数据表明， 涉及ATF 4、MITF和PGC-1α转录的特定黑色素瘤亚群的动态反馈回路 因素ATF 4-MITF-PGC-1α轴对内质网应激、营养剥夺和黑色素瘤驱动因子有反应 突变，并调节对靶向治疗、ROS应激和代谢应激的反应。这个项目是 PGC-1家族的转录辅助调节因子PGC-1α、PGC-1β和PRC在这些过程中的作用， 流程.最近的证据表明，PGC-1α是线粒体生物发生的主要调节因子， 在黑色素瘤的一个子集中，MITF与MITF一起上调。PGC-1α表达升高与 线粒体含量和耗氧率增加。有趣的是，在这种情况下， 黑色素瘤的一个亚群导致线粒体含量、氧消耗进一步增加，并诱导 对线粒体呼吸抑制剂的敏感性ER应激/未折叠蛋白之间的相互作用 反应和PGC-1α/线粒体将在项目1中表征。线粒体和PGC-1α也整合 与谷氨酰胺代谢相关的信号，项目3的重点。我们假设线粒体功能 由PGC-1因子的活性决定的能力，协调细胞应激反应， 用于定义对临床干预的尿道靶向药物的敏感性。到 为了表征PGC-1α、PGC-1β、PRC和线粒体功能在黑色素瘤中的作用，我们将（1）确定 MITF/PGC-1α/ERRα通路在黑色素瘤形成的代谢调节中的功能作用， 治疗反应和（2）评估PGC-1β和PRC在黑色素瘤代谢调节、应激 反应和对治疗干预的敏感性。我们的研究将与项目1紧密结合， 3，并将需要使用核心B和C。

SUMMARY – PROJECT 2: PGC-1 SIGNALING AND MITOCHONDRIAL STRESS IN MELANOMA During the process of melanoma formation, progression, and treatment, dramatic changes in metabolism occur and are required for the evolving energetic and biosynthetic needs of rapidly proliferating cells. Mitochondria serve as a central integration point for this metabolic re-programming; regulating ATP synthetic capacity, redox signaling, and biosynthetic capability. Preliminary data presented in this P01 application demonstrate a dynamic feedback circuit in specific melanoma subsets involving ATF4, MITF, and PGC-1α transcription factors. The ATF4–MITF–PGC-1α axis is responsive to ER stress, nutrient deprivation, and melanoma driver mutations, and regulates responses to targeted therapies, ROS stress, and metabolic stress. This Project is focused on the role of the PGC-1 family of transcription coregulators, PGC-1α, PGC-1β, and PRC, in these processes. Recent evidence indicates that PGC-1α, a master regulator of mitochondrial biogenesis and function, is upregulated in a subset of melanomas together with MITF. Elevated PGC-1α expression correlates with increased mitochondrial content and oxygen consumption rates. Interestingly, inhibition of BRAF in this subset of melanomas results in further increase in mitochondrial content, oxygen consumption and induces sensitivity to mitochondrial respiratory inhibitors. The interplay between the ER stress/unfolded protein response and PGC-1α/mitochondria will be characterized in Project 1. Mitochondria and PGC-1α also integrate signals related to glutamine metabolism, a focus of Project 3. We hypothesize that mitochondrial functional capacity, as determined by the activity of PGC-1 factors, coordinates cellular stress responses and can be used to define susceptibility to mitochondrial-targeted agents for clinical intervention. To characterize the role of PGC-1α, PGC-1β, PRC and mitochondrial function in melanoma, we will (1) determine the functional role of the MITF/PGC-1α/ERRα pathway in the metabolic regulation of melanoma formation and treatment response and (2) evaluate the role of PGC-1β and PRC in melanoma metabolic regulation, stress responses, and sensitivity to therapeutic intervention. Our studies will be closely integrated with Projects 1 and 3, and will require the use of Cores B and C.