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HIF‐1‐dependent transcriptional activity is required for oxygen‐mediated HIF‐1α degradation
Author(s) -
Berra Edurne,
Richard Darren E,
Gothié Emmanuel,
Pouysségur Jacques
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02159-7
Subject(s) - proteasome , transcription factor , ubiquitin , hypoxia inducible factors , phosphorylation , chemistry , protein degradation , microbiology and biotechnology , kinase , hypoxia inducible factor 1 , degradation (telecommunications) , transcriptional activity , transcription (linguistics) , hypoxia (environmental) , homeostasis , biochemistry , oxygen , biology , gene , telecommunications , linguistics , philosophy , organic chemistry , computer science
Hypoxia‐inducible factor‐1α (HIF‐1α) plays a central role in oxygen homeostasis. In normoxia, HIF‐1α is a short lived protein, whereas hypoxia rapidly increases HIF‐1α protein levels by relaxing its ubiquitin–proteasome‐dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF‐1α, does not modulate the degradation/stabilization profile of HIF‐1α. However, we present evidence that the rate of HIF‐1α degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF‐1α is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF‐1‐dependent transcriptional activity. In keeping with these findings, we postulate that HIF‐1α is targetted to the proteasome via a HIF‐1α proteasome targetting factor (HPTF) which expression is directly under the control of HIF‐1‐mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel–Lindau protein (pVHL).