Regulation of the Drosophila hypoxia-inducible factor alpha Sima by CRM1-dependent nuclear export.

Hypoxia-inducible factor alpha (HIF-alpha) proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional coactivator recruitment, and subcellular localization. It was previously reported that these transcription factors are mainly nuclear in hypoxia and cytoplasmic in normoxia, but so far the molecular basis of this regulation ...
is unclear. We show here that the Drosophila melanogaster HIF-alpha protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal and two functional nuclear export signals (NESs). These NESs are in the Sima basic helix-loop-helix (bHLH) domain and promote CRM1-dependent nuclear export. Site-directed mutagenesis of either NES provoked Sima nuclear retention and increased transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and probably functional in the bHLH domains of several bHLH-PAS proteins. We propose that rapid nuclear export of Sima regulates the duration of cellular responses to hypoxia.
Mesh Terms:
Active Transport, Cell Nucleus, Amino Acid Sequence, Animals, Animals, Genetically Modified, Conserved Sequence, DNA-Binding Proteins, Drosophila Proteins, Drosophila melanogaster, Evolution, Molecular, Hypoxia-Inducible Factor 1, alpha Subunit, Karyopherins, Models, Biological, Molecular Sequence Data, Nuclear Export Signals, Nuclear Localization Signals, Protein Processing, Post-Translational, Receptors, Cytoplasmic and Nuclear, Sequence Homology, Amino Acid, Transcription, Genetic
Mol Cell Biol
Date: May. 01, 2008
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