Induction of the von Hippel-Lindau tumor suppressor gene by late hypoxia limits HIF-1 expression

Hypoxia-inducible factor (HIF) remains the central focus of oxygen sensing during hypoxia. HIF is a heterodimeric transcription factor consisting of an oxygen-regulated alpha- and a constitutively expressed beta subunit. The von Hippel-Lindau tumor suppressor (pVHL) is a component of the E3 ubiquitin ligase complex and targets HIF-alpha to proteasomal degradation, but also is known to exert a significant control on HIF transactivation activity. However, the understanding of the full interaction between HIF and pVHL has been hindered by a lack in the understanding of pVHL regulation. Here, we report that pVHL itself is induced in prolonged hypoxia in a kinetic that parallels the observed downregulation of HIF-1 alpha protein under such conditions. In addition, we document direct HIF-1 alpha binding to the VHL promoter and identify a functional hypoxia response element (HRE) within the VHL promoter. Such induction of pVHL in hypoxia furthermore has functional implications for the HIF dependent hypoxic response, implicating a physiologically relevant feedback mechanism. These results provide an intriguing model, whereby HIF self-regulates expression through VHL and highlight the role of pVHL as a unifying mechanism of HIF regulation.