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Mol. Cell. Biol. doi:10.1128/MCB.01027-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of the Drosophila HIF- protein Sima by CRM1-dependent nuclear export

Instituto Leloir and FBMC, FCEyN, Universidad de Buenos Aires; CONICET. Patricias Argentinas 435, Buenos Aires (1405). ARGENTINA; Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, S-106 96 Stockholm, SWEDEN

^* To whom correspondence should be addressed. Email: pwappner{at}leloir.org.ar.

	Abstract

HIF- proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional co-activator 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 HIF- protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal (NLS) and two functional nuclear export signals (NESs). These NES are in the Sima 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.