Zhang Huafeng, Gao Ping, Fukuda Ryo, Kumar Ganesh, Krishnamachary Balaji, Zeller Karen I, Dang Chi V, Semenza Gregg L
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cancer Cell. 2007 May;11(5):407-20. doi: 10.1016/j.ccr.2007.04.001.
Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.
许多癌细胞的特征是即使在有氧条件下糖酵解增加而呼吸作用降低。这种代谢重编程的分子机制尚不清楚。在此我们表明，缺氧诱导因子1（HIF-1）对缺乏冯·希佩尔-林道肿瘤抑制因子（VHL）的肾癌细胞中线粒体生物发生和氧消耗起负调节作用。HIF-1通过两种机制抑制C-MYC活性来介导这些效应。首先，HIF-1结合并激活MXI1基因的转录，该基因编码C-MYC转录活性的一种抑制因子。其次，HIF-1促进不依赖MXI-1的、蛋白酶体依赖性的C-MYC降解。我们证明编码辅激活因子PGC-1β的基因转录是C-MYC依赖性的，并且PGC-1β表达缺失是导致VHL缺陷型肾癌细胞呼吸作用降低的一个主要因素。
