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Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1 alpha by MAPK
dc.creator | Mylonis, I. | en |
dc.creator | Chachami, G. | en |
dc.creator | Paraskeva, E. | en |
dc.creator | Simos, G. | en |
dc.date.accessioned | 2015-11-23T10:40:19Z | |
dc.date.available | 2015-11-23T10:40:19Z | |
dc.date.issued | 2008 | |
dc.identifier | 10.1074/jbc.M803081200 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | http://hdl.handle.net/11615/31240 | |
dc.description.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. | en |
dc.source | Journal of Biological Chemistry | en |
dc.source.uri | <Go to ISI>://WOS:000259719200033 | |
dc.subject | HYPOXIA-INDUCIBLE FACTOR-1-ALPHA | en |
dc.subject | TRANSCRIPTIONAL ACTIVITY | en |
dc.subject | HIF | en |
dc.subject | HYDROXYLASES | en |
dc.subject | HIF-1-ALPHA | en |
dc.subject | OXYGEN | en |
dc.subject | PHOSPHORYLATION | en |
dc.subject | LOCALIZATION | en |
dc.subject | RECEPTOR | en |
dc.subject | ACCUMULATION | en |
dc.subject | DEGRADATION | en |
dc.subject | Biochemistry & Molecular Biology | en |
dc.title | Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1 alpha by MAPK | en |
dc.type | journalArticle | en |
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