Calcium signaling stimulates translation of HIF-alpha during hypoxia.
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.
Hui
Anna S
AS
Department of Genome Science, Genome Research Institute, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0505, USA.
Bauer
Amy L
AL
Striet
Justin B
JB
Schnell
Phillip O
PO
Czyzyk-Krzeska
Maria F
MF
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000032:analysis; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001596:Benzylamines / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D020013:Calcium Signaling; D002227:Carbazoles / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007211:Indoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012315:RNA Caps / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; D000096926:Benzenesulfonamides
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001596:Benzylamines; D002070:Butadienes; D002227:Carbazoles; D003513:Cycloheximide; D005419:Flavonoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D015759:Ionomycin; D007546:Isoquinolines; D009570:Nitriles; D051571:Protein Kinase C-alpha; D011494:Protein Kinases; D011500:Protein Synthesis Inhibitors; D012315:RNA Caps; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020123:Sirolimus; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C497398:ARNT protein, rat; C425780:KN 92; C113580:U 0126; C081021:Go 6976; C072105:KN 93; D000096926:Benzenesulfonamides; C546842:MTOR protein, human; C546845:mTOR protein, rat; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one