Huang L E
Department of Neurosurgery, University of Utah, Salt Lake City, UT 84132, USA.
Cell Death Differ. 2008 Apr;15(4):672-7. doi: 10.1038/sj.cdd.4402302. Epub 2008 Jan 11.
The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1alpha. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the proto-oncoprotein c-Myc appears to be the diametrical opposite of HIF-1alpha in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-alpha-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-alpha engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of c-Myc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-alpha for the regulation of hypoxia-responsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter.
在过去十年对缺氧反应的研究中，由于缺氧诱导转录因子HIF-1α的鉴定和分子克隆，我们对细胞在分子水平上如何应对缺氧应激有了相当深入的了解。自那时起，已鉴定出许多靶基因来解释缺氧反应的各个方面，包括血管生成和糖酵解。然而，关于缺氧控制癌细胞增殖、遗传不稳定性、线粒体生物发生和氧化呼吸的机制，仍存在一些基本问题。尽管原癌蛋白c-Myc在大多数这些过程中似乎与HIF-1α截然相反，但最近的研究表明，c-Myc是缺氧反应中HIF-α-c-Myc分子途径的一个组成部分。研究表明，HIF-α通过各种机制与Myc相互作用，以实现细胞存活所需的氧稳态。本文重点关注c-Myc在缺氧反应中的复杂作用，讨论HIF-α控制c-Myc活性以调节缺氧反应基因的各种机制，并强调基因表达的结果显然取决于缺氧条件、细胞背景和基因启动子。
