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Induction of the von Hippel‐Lindau tumor suppressor gene by late hypoxia limits HIF‐1 expression
Author(s) -
Karhausen Jörn,
Kong Tianqing,
Narravula Sailaja,
Colgan Sean P.
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20489
Subject(s) - transactivation , ubiquitin ligase , transcription factor , hif1a , downregulation and upregulation , hypoxia inducible factors , hypoxia inducible factor 1 , hypoxia (environmental) , suppressor , protein subunit , microbiology and biotechnology , ubiquitin , g alpha subunit , chemistry , transcription (linguistics) , aryl hydrocarbon receptor nuclear translocator , biology , cancer research , angiogenesis , gene , biochemistry , oxygen , linguistics , philosophy , organic chemistry , aryl hydrocarbon receptor
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‐α 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‐1α protein under such conditions. In addition, we document direct HIF‐1α 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. © 2005 Wiley‐Liss, Inc.