The HIF and other quandaries in VHL disease

Oncogene. 2018 Jan 11;37(2):139-147. doi: 10.1038/onc.2017.338. Epub 2017 Sep 18.

Abstract

Mutations in VHL underlie von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome with several subtypes depending on the risk of developing certain combination of classic features, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma and pheochromocytoma. Although numerous potential substrates and functions of pVHL have been described over the past decade, the best-defined role of pVHL has remained as the negative regulator of the heterodimeric hypoxia-inducible factor (HIF) transcription factor via the oxygen-dependent ubiquitin-mediated degradation of HIF-α subunit. Despite the seminal discoveries that led to the molecular elucidation of the mammalian oxygen-sensing VHL-HIF axis, which have provided several rational therapies, the mechanisms underlying the complex genotype-phenotype correlation in VHL disease are unclear. This review will discuss and highlight the studies that have provided interesting insights as well as uncertainties to the underlying mechanisms governing VHL disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenal Gland Neoplasms / genetics
  • Adrenal Gland Neoplasms / pathology
  • Adrenal Gland Neoplasms / therapy
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / therapy
  • Hemangioblastoma / genetics
  • Hemangioblastoma / pathology
  • Hemangioblastoma / therapy
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / pathology
  • Kidney Neoplasms / therapy
  • Mice
  • Oxygen / metabolism*
  • Pheochromocytoma / genetics
  • Pheochromocytoma / pathology
  • Proteolysis
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / pathology*
  • von Hippel-Lindau Disease / therapy

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human
  • Oxygen

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