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      HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.

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          Abstract

          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.

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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          Elsevier BV
          1535-6108
          1535-6108
          May 2007
          : 11
          : 5
          Affiliations
          [1 ] Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          Article
          S1535-6108(07)00115-8
          10.1016/j.ccr.2007.04.001
          17482131
          a6f50de4-635e-4998-8c00-efe79b2a9eef
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