Transport of hypoxia-inducible factor HIF-1{alpha} into the nucleus involves importins 4 and 7
- Laboratory of Biochemistry, School of Medicine, University of Thessaly, Mezourlo, 41110 Larissa (Greece)
- Laboratory of Physiology, School of Medicine, University of Thessaly, Mezourlo, 41110 Larissa (Greece)
- ZMBH, Universitaet Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg (Germany)
Hypoxia-inducible transcription factor 1 (HIF-1) mediates the cellular response to hypoxia. HIF-1 activity is controlled via the synthesis, degradation or intracellular localization of its {alpha} subunit. HIF-1{alpha} contains a C-terminal bipartite basic NLS that interacts with importins {alpha}. We have recently shown that HIF-1{alpha} also contains an atypical hydrophobic CRM1- and phosphorylation-dependent NES and can therefore shuttle in and out of the nucleus. We now report that C-terminal NLS mutants of HIF-1{alpha} can still enter the nucleus when CRM1-dependent nuclear export is inhibited, indicating that HIF-1{alpha} contains an additional functional nuclear import signal. Using an in vitro nuclear import assay, we further show that importins 4 and 7 accomplish nuclear import of HIF-1{alpha} more efficiently than the classical importin {alpha}/{beta} NLS receptor. Binding assays confirmed the specific physical interaction between HIF-1{alpha} and importins 4 and 7. Moreover, the interaction of importin 7 with HIF-1{alpha} is mapped at its N-terminal part encompassing the bHLH-PAS{sub A} domain. By expressing functional HIF-1 in yeast, we show that Nmd5, the yeast orthologue of importin 7, is required for HIF-1{alpha} nuclear accumulation and activity. Taken together, our data show that shuttling of HIF-1{alpha} between cytoplasm and nucleus is a complex process involving several members of the nuclear transport receptor family.
- OSTI ID:
- 22199897
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 390, Issue 2; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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