Hypoxic signaling is a central modulator of cellular physiology in
cancer. Core members of
oxygen-sensing pathway including the
von Hippel-Lindau tumor suppressor protein (pVHL) and the
hypoxia inducible factor (HIF)
transcription factors have been intensively studied, but improved organismal models might speed advances for both pathobiologic understanding and therapeutic modulation. To study HIF signaling during
tumorigenesis and development in zebrafish, we developed a unique in vivo reporter for
hypoxia, expressing EGFP driven by
prolyl hydroxylase 3 (phd3) promoter/regulatory elements. Modulation of HIF pathway in Tg(phd3::EGFP) embryos showed a specific role for hypoxic signaling in the transgene activation. Zebrafish vhl mutants display a systemic
hypoxia response, reflected by strong and ubiquitous transgene expression. In contrast to human VHL patients, heterozygous Vhl mice and vhl zebrafish are not predisposed to
cancer. However, upon exposure to dimethylbenzanthracene (DMBA), the vhl heterozygous fish showed an increase in the occurrence of hepatic and intestinal
tumors, a subset of which exhibited strong transgene expression, suggesting loss of Vhl function in these
tumor cells. Compared with control fish, DMBA-treated vhl heterozygous fish also showed an increase in
proliferating cell nuclear antigen-positive renal tubules. Taken together, our findings establish Vhl as a genuine
tumor suppressor in zebrafish and offer this model as a tool to noninvasively study VHL and HIF signaling during
tumorigenesis and development.