REGULATION OF THE DROSOPHILA HIF-á SIMA BY CRM1-DEPENDENT NUCLEAR EXPORT

ROMERO N.M.; ROTH P.; IRISARRI M.; CAUEHRFF A.; SAMAKOVLIS C.; WAPPNER P

Viena-Austria

Congreso; 20th European Drosophila Research Conference.; 2007

HIF-á 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-á protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified two nuclear export signals (NESs) in the Sima bHLH domain that promote CRM1-dependent nuclear export, both in cell culture and in vivo. Site directed mutagenesis of either NES provoked Sima nuclear retention and increased its transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and functional in the bHLH domains of several bHLH-PAS proteins that are activated in response to different environmental stimuli. We propose that rapid nuclear export of the bHLH-PAS factors regulate the duration of cellular responses to external signals