Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-55581
Wollenick, K; Hu, J; Kristiansen, G; Schraml, P; Rehrauer, H; Berchner-Pfannschmidt, U; Fandrey, J; Wenger, R H; Stiehl, D P (2012). Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling. Nucleic Acids Research, 40(5):1928-1943.
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The human prolyl-4-hydroxylase domain (PHD) proteins 1-3 are known as cellular oxygen sensors, acting via the degradation of hypoxia-inducible factor (HIF) α-subunits. PHD2 and PHD3 genes are inducible by HIFs themselves, suggesting a negative feedback loop that involves PHD abundance. To identify novel regulators of the PHD2 gene, an expression array of 704 transcription factors was screened by a method that allows distinguishing between HIF-dependent and HIF-independent promoter regulation. Among others, the E-twenty six transcription factor ETS translocation variant 4 (ETV4) was found to contribute to PHD2 gene expression particularly under hypoxic conditions. Mechanistically, complex formation between ETV4 and HIF-1/2α was observed by mammalian two-hybrid and fluorescence resonance energy transfer analysis. HIF-1α domain mapping, CITED2 overexpression and factor inhibiting HIF depletion experiments provided evidence for cooperation between HIF-1α and p300/CBP in ETV4 binding. Chromatin immunoprecipitation confirmed ETV4 and HIF-1α corecruitment to the PHD2 promoter. Of 608 hypoxically induced transcripts found by genome-wide expression profiling, 7.7% required ETV4 for efficient hypoxic induction, suggesting a broad role of ETV4 in hypoxic gene regulation. Endogenous ETV4 highly correlated with PHD2, HIF-1/2α and several established markers of tissue hypoxia in 282 human breast cancer tissue samples, corroborating a functional interplay between the ETV4 and HIF pathways.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology|
04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||20 Jan 2012 21:35|
|Last Modified:||06 Dec 2013 18:24|
|Publisher:||Oxford University Press|
|Citations:||Web of Science®. Times cited: 4|
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