Recently, work on the mechanism of action of the von Hippel-Lindau tumour suppressor protein (pVHL) and studies on hypoxic gene regulation have converged, providing insights into both cellular oxygen sensing and cancer pathogenesis. pVHL is the recognition component of the E3-ubiquitin ligase complex involved in the degradation of hypoxia-inducible factor-1 (HIF) alpha-subunits, a process regulated by oxygen availability and blocked by disease causing pVHL mutations. In normoxic cells, pVHL targeting of HIF-alpha subunits follows hydroxylation of critical HIF prolyl residues by a group of oxygen, 2-oxoglutarate- and iron-dependent enzymes. In this review, we outline current understanding of HIF/pVHL/prolyl hydroxylase pathway and consider the implications for VHL-associated cancer.

Type

Journal article

Journal

Semin Cancer Biol

Publication Date

02/2003

Volume

13

Pages

83 - 89

Keywords

DNA-Binding Proteins, Gene Expression Regulation, Genes, Tumor Suppressor, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Ligases, Neoplasms, Nuclear Proteins, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease