Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 41, Pages 27620-27627Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M803081200
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- European Social Fund and National Resources
- EPEAEK II-PYTHAGORAS
- Greek Ministry of National Education and Religious Affairs
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Hypoxia-inducible factor 1 (HIF-1) is the key transcriptional activator of hypoxia-inducible genes and an important anti-cancer target. Its regulated subunit, HIF-1 alpha, is controlled by oxygen levels and major signaling pathways. We reported previously that phosphorylation of Ser(641/643) by p42/44 MAPK is essential for HIF-1 alpha nuclear accumulation and activity. We now show that a fragment of HIF-1 alpha (amino acids 616-658), termed MAPK target domain, contains a nuclear export signal (NES), which has atypical hydrophobic residue spacing. Localization, reporter gene, and co-immunoprecipitation assays demonstrate that the identified NES interacts with CRM1 in a phosphorylation-sensitive manner. Furthermore, disruption of the NES (I637A/L638A/I639A) restores nuclear localization and activity of nonphosphorylated HIF-1 alpha and renders it largely resistant to inhibition of MAPK, an effect reproduced by a phosphomimetic mutation (S641E). As these data predict, overexpression of wildtype or mutant (S641A/S643A) MAPK target domain in HeLa cells modulates the activity and subcellular distribution of endogenous HIF-1 alpha. Wesuggest that control of HIF-1 alpha nuclear transport represents an important MAPK-dependent regulatory mechanism.
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