Metabolic Outcomes of c-MYC, p53 and mTOR Regulation by HIF

低水平的氧（O{2}）或缺氧引起对细胞代谢大分子生物合成、增殖和基因表达的深刻适应性影响。缺氧诱导因子（hypoxia inducible factors，HIFs）是一类对氧敏感的转录因子家族，其启动子为增强子，可激活具有缺氧反应元件（hypoxia response elements，HRE）的基因。两种高度相关的HIF蛋白，HIF-1a和HIF-2a调节大量介导细胞凋亡的靶基因。 低氧适应缺氧还影响协调细胞内代谢生长的三个关键途径，即c-Myc，mTOR和p53。尽管HIF-1a和HIF-2a经常调节对O{2}饥饿的重叠反应，但它们在c-Myc、mTOR和p53调节中表现出相反的作用。我们假设HIF和这三种途径之间的重叠对于癌细胞适应氧气和营养物质的提取是重要的。为了提高我们对癌细胞代谢适应的理解，我们 提议：（1）确定HIF-1a和HIF-2a如何不同地影响肾癌细胞中的c-Myc和代谢，（2）表征HIF-1a与HIF-2a对mTOR通路和肾癌的调节，和（3）确定HIF-2a对p53的调节是否促进肾癌进展和对治疗的抗性。由于肿瘤血管的血管功能差，实体瘤内的细胞经常遇到O{2}剥夺。该提案的最终目标是更好地定义癌细胞代谢的低氧调节，并开发旨在对抗这些病变的独特代谢和生理学的新疗法。

Low levels of oxygen (O{2}), or hypoxia elicit profound adaptive effects on cellular metabolism macromolecular biosynthesis, proliferation, and gene expression. Most transcriptional responses to O{2} deprivation are regulated by hypoxia inducible factors (HIFs), a family of O{2} sensitive transcription factors that transactivate genes with hypoxia response elements (HREs) and their promoters are enhancers. Two highly related HIF proteins, HIF-1a, and HIF-2a regulate a large number of target genes that mediate hypoxic adaptations. Hypoxia also influences three critical pathways that coordinate intracellular metabolism growth, namely c-Myc, mTOR, and p53. Whereas HIF-1a and HIF-2a frequently regulate overlapping responses to O{2} starvation, they exhibit opposing roles in c-Myc, mTOR, and p53 regulation. We hypothesize that overlap between the HIFs and these three pathways is important to cancer cell adaptation to oxygen and nutrient withdraw. To enhance our understanding of cancer cell metabolic adaptations, we propose to: (1) define how HIF-1a and HIF-2a differentially impact c-Myc and metabolism in renal carcinoma cells, (2) characterize HIF-1a versus HIF-2a modulation of the mTOR pathway and renal carcinoma, and (3) determine if HIF-2a regulation of p53 promotes renal carcinoma progression and resistance to therapy. Cells within solid tumors frequently encounter O{2} deprivation given the poor vascular function of tumor blood vessels. The ultimate goal of this proposal is to better define hypoxic regulation of cancer cell metabolism and develop novel therapies designed to combat the unique metabolism and physiology of these lesions.