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(The FASEB Journal. 2006;20:466-475.)
© 2006 FASEB

Calcium signaling stimulates translation of HIF-{alpha} during hypoxia

Anna S. Hui1, Amy L. Bauer1, Justin B. Striet, Phillip O. Schnell and Maria F. Czyzyk-Krzeska2

Department of Genome Science, Genome Research Institute, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

2Correspondence: Department of Genome Science, University of Cincinnati College of Medicine, 2180 E Galbraith Rd., Cincinnati, OH 45267-0505, USA. E-mail: maria.czyzykkrzeska{at}uc.edu

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-1{alpha} and -2{alpha} 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 ~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.—Hui, A. S., Bauer, A. L., Striet, J. B., Schnell, P. O., Czyzyk-Krzeska, M. F. Calcium signaling stimulates translation of HIF-{alpha} during hypoxia.


Key Words: protein kinase C • oxygen-sensitive cells • protein translation • carotid body • PC12 cells




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