Abstract
Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3′ UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.
Highlights
Animals can adapt to variations of oxygen levels by modifying their transcription profile
In this study we show that dMsi is a novel inhibitor of Hypoxia Inducible Factor (HIF)-dependent responses to hypoxia in Drosophila. dMsi recognizes a Musashi Binding Elements (MBEs) within the 3 untranslated region (3 UTR) of sima mRNA and mediates its translational repression in normoxic conditions. dMsi is downregulated in hypoxia, lifting Sima repression and contributing to trigger HIF-dependent gene expression
We have established a role of the RNA binding protein dMusashi in the regulation of mRNA translation of the hypoxia inducible factor alpha subunit (HIF␣)
Summary
Animals can adapt to variations of oxygen levels by modifying their transcription profile. HIF␣ is rapidly degraded in normoxia and stabilized in hypoxia, being its degradation dependent on the hydroxylation of key prolyl residues localized in the HIF␣ oxygen-dependent degradation domain [3,4]. Hydroxylation of these prolines is mediated by specific prolyl4-hydroxylases, termed PHDs, that utilise molecular oxygen as a co-substrate for catalysis, and are considered oxygen sensors [5,6]. The bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are respectively the Drosophila HIF␣ and HIF homologs [7], while the fatiga gene encodes the Drosophila PHD isoforms that control Sima stability in an oxygen dependent manner [8,9]. The Drosophila HIF system has been shown to control adaptation to hypoxia in vivo through mechanisms identical to those operating in mammalian systems [10]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call