title: A zebrafish model for VHL and hypoxia signaling.
abstract: The von Hippel-Lindau (VHL) tumor suppressor gene encodes an adaptor protein that regulates an array of transcription-dependent and -independent cellular and physiological processes. Mutations in this gene cause VHL disease, congenital polycythemia, and several sporadic tumor types. The last 15 years of fundamental and clinical research have helped define the phenotypic spectrum of VHL-associated diseases and have introduced new cellular functions for pVHL. Here, we review the current knowledge of VHL function, and the different animal models for VHL disease, with a particular focus on the zebrafish. Zebrafish vhl mutants develop key aspects of the human disease condition, including activation of the hypoxia-inducible factor (HIF) signaling pathway, polycythemia, excessive neovascularization, macular edema, and pronephric abnormalities. The zebrafish vhl model offers a platform for the identification of genetic pathways, modifiers, and interactors involved in the development of VHL-associated neoplasms. Vhl mutants represent a unique and clinically relevant in vivo model for studying genotype-phenotype correlations and the identification of prognostic biomarkers. The amenability of zebrafish for chemical genetic screens will not only be helpful to identify novel therapeutic agents but may also reveal novel processes that require regulation by VHL.
authors.affiliation: Department of Medical Oncology, University Medical Center, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Rooijen
authors.forename: Kirankumar
authors.initials: K
authors.lastname: Santhakumar
authors.forename: Ive
authors.initials: I
authors.lastname: Logister
authors.forename: Emile
authors.initials: E
authors.lastname: Voest
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.forename: Rachel
authors.initials: R
authors.lastname: Giles
authors.forename: Fredericus
authors.initials: F
authors.lastname: van Eeden
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D056726:Genetic Association Studies; D005816:Genetic Complementation Test / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011086:Polycythemia / Q000235:genetics* / Q000473:pathology; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D025521:Tumor Suppressor Proteins; C542158:Vhl protein, zebrafish; D029961:Zebrafish Proteins