Calcium signaling stimulates translation of HIF- during hypoxia

Department of Genome Science, Genome Research Institute, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0505, USA.
The FASEB Journal (Impact Factor: 5.04). 04/2006; 20(3):466-75. DOI: 10.1096/fj.05-5086com
Source: PubMed


Hypoxia-inducible factors (HIFs) are ubiquitous transcription factors that mediate adaptation to hypoxia by inducing specific sets of target genes. It is well accepted that hypoxia induces accumulation and activity of HIFs by causing stabilization of their alpha subunits. We have demonstrated that hypoxia stimulates translation of HIF-1alpha and -2alpha proteins by distributing HIF-alpha mRNAs to larger polysome fractions. This requires influx of extracellular calcium, stimulation of classical protein kinase C-alpha (cPKC-alpha), and the activity of mammalian target of rapamycin, mTOR. The translational component contributes to approximately 40-50% of HIF-alpha proteins accumulation after 3 h of 1% O2. Hypoxia also inhibits general protein synthesis and mTOR activity; however, cPKC-alpha inhibitors or rapamycin reduce mTOR activity and total protein synthesis beyond the effects of hypoxia alone. These data show that during general inhibition of protein synthesis by hypoxia, cap-mediated translation of selected mRNAs is induced through the mTOR pathway. We propose that calcium-induced activation of cPKC-alpha hypoxia partially protects an activity of mTOR from hypoxic inhibition. These results provide an important physiologic insight into the mechanism by which hypoxia-stimulated influx of calcium selectively induces the translation of mRNAs necessary for adaptation to hypoxia under conditions repressing general protein synthesis.

    • "Prior studies of HIF1a regulation under hypoxia have largely focused on transcriptional activation or protein stabilization. Stress-induced translation of HIF1a remains poorly understood, even though it may play a critical regulatory role under hypoxia (Hui et al., 2006). YB-1 is a prominent RNAbinding protein and a well-established regulator of mRNA translation (Eliseeva et al., 2011). "
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    • "Both ROS and Ca 2+ are important signaling molecules that regulate the response to hypoxia. Ca 2+ modulates cell contraction, cell proliferation and growth (Shimoda and Undem 2010; Wang and Zheng 2010), and calcium signaling will stimulate the translation of HIF-alpha, an ubiquitous transcription factors that mediates adaptation to hypoxia (Hui et al. 2006) (fig. 4). "
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