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Molecular and Cellular Biology, May 2008, p. 3410-3423, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01027-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of the Drosophila Hypoxia-Inducible Factor {alpha} Sima by CRM1-Dependent Nuclear Export {triangledown}

Nuria M. Romero,1 Maximiliano Irisarri,1 Peggy Roth,2 Ana Cauerhff,1 Christos Samakovlis,2 and Pablo Wappner1*

Instituto Leloir and FBMC, FCEyN, Universidad de Buenos Aires, CONICET, Patricias Argentinas 435, Buenos Aires 1405, Argentina,1 Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, S-106 96 Stockholm, Sweden2

Received 11 June 2007/ Returned for modification 28 August 2007/ Accepted 25 February 2008

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.

* Corresponding author. Mailing address: Patricias Argentinas 435, Buenos Aires 1405, Argentina. Phone: (54-11) 52387500. Fax: (54-11) 5238-7501. E-mail: pwappner{at}leloir.org.ar

{triangledown} Published ahead of print on 10 March 2008.

Molecular and Cellular Biology, May 2008, p. 3410-3423, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01027-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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