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Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1 alpha by MAPK

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Autore
Mylonis, I.; Chachami, G.; Paraskeva, E.; Simos, G.
Data
2008
DOI
10.1074/jbc.M803081200
Soggetto
HYPOXIA-INDUCIBLE FACTOR-1-ALPHA
TRANSCRIPTIONAL ACTIVITY
HIF
HYDROXYLASES
HIF-1-ALPHA
OXYGEN
PHOSPHORYLATION
LOCALIZATION
RECEPTOR
ACCUMULATION
DEGRADATION
Biochemistry & Molecular Biology
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Abstract
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.
URI
http://hdl.handle.net/11615/31240
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