Affiliation:
1. Laboratory of Biochemistry, Faculty of Medicine University of Thessaly Larissa Greece
2. Gerald Bronfman Department of Oncology, Faculty of Medicine McGill University Montreal QC Canada
Abstract
Hypoxia‐inducible factor‐1, a heterodimer of alpha (HIF‐1α) and beta (HIF‐1β or ARNT) subunits, is a major regulator of the transcriptional response to hypoxia. However, HIF‐1α, the oxygen‐regulated subunit, also exerts nontranscriptional functions through interaction with proteins other than ARNT. We have previously shown that the subcellular localization and protein interactions of HIF‐1α are controlled by ERK‐mediated phosphorylation at Ser641/643. When HIF‐1α is modified at these sites, it is nuclear, binds to ARNT, interacts with nucleophosmin 1 (NPM1) and activates transcription of hypoxia‐target genes. On the contrary, unmodified HIF‐1α is bound by chromosomal region maintenance 1 (CRM1), exits the nucleus and, via its association with mortalin, is targeted to the mitochondria to form an antiapoptotic complex. To further characterize the latter function, recombinant fragments of HIF‐1α and mortalin were used for in vitro binding assays and immunoprecipitation experiments to map the respective binding sites and show that their interaction is direct and functional. We could also show that embelin, a natural product and known inhibitor of the mortalin‐p53 interaction, also disrupts the mortalin‐HIF‐1α association and, furthermore, removes unmodified HIF‐1α from mitochondria. Mitochondrial dissociation of HIF‐1α, either by embelin or overexpression of a HIF‐1α peptide harbouring the mortalin binding site, under stress conditions leads to mitochondrial localization of the pro‐apoptotic protein B‐cell lymphoma 2‐associated X protein (Bax) and induction of apoptosis. We suggest that when ERK activity is low under hypoxia, binding of HIF‐1α to mortalin inhibits mitochondrial recruitment of Bax and protects cells from apoptotic cell death.
Funder
Bodossaki Foundation
State Scholarships Foundation
Hellenic Foundation for Research and Innovation
Subject
Cell Biology,Molecular Biology,Biochemistry
Cited by
2 articles.
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