HIF-1 mediates the Warburg effect in clear cell renal carcinoma.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. O(2)-dependent hydroxylation of two proline residues in the HIF-1alpha subunit is necessary for the binding of the von Hippel-Lindau (VHL) protein, which is a component of a ubiquitin protein ligase that ubiquitinates HIF-1alpha, leading to its degradation by the proteasome. In the majority of cases of the clear cell type of renal carcinoma, both VHL genes are inactivated by mutation or epigenetic silencing, leading to dysregulated HIF-1 transcriptional activity. VHL loss-of-function leads, under aerobic conditions, to a HIF-1-dependent reprogramming of glucose and energy metabolism that includes increased glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration. These findings delineate for the first time the molecular mechanisms underlying the Warburg effect in a human cancer.
Semenza
Gregg L
GL
Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gsemenza@jhmi.edu
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007680:Kidney Neoplasms / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011485:Protein Binding; D019289:Pyruvic Acid / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D019289:Pyruvic Acid; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D010100:Oxygen