Journal ArticleDOI
Calcium signaling stimulates translation of HIF-α during hypoxia
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TLDR
The data show that during general inhibition of protein synthesis by hypoxia, cap‐mediated translation of selected mRNAs is induced through the mTOR pathway, and it is proposed that calcium‐induced activation of cPKC‐αhypoxia partially protects an activity of mTOR from hypoxic inhibition.Abstract:
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.read more
Citations
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With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging.
Pankaj Kapahi,Di Chen,Aric N. Rogers,Subhash D. Katewa,Patrick Wai-Lun Li,Emma Lynn Thomas,Lutz Kockel +6 more
TL;DR: How modulating TOR signaling slows aging through downstream processes including mRNA translation, autophagy, endoplasmic reticulum (ER) stress signaling, stress responses, and metabolism is discussed.
Journal ArticleDOI
The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production
Eric L. Bell,Tatyana A. Klimova,James Eisenbart,Carlos T. Moraes,Michael P. Murphy,G. R. Scott Budinger,Navdeep S. Chandel +6 more
TL;DR: Genetic and pharmacologic evidence is provided that the Qo site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1α protein.
Journal ArticleDOI
Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis.
Satoshi Fujita,Satoshi Fujita,Takashi Abe,Micah J. Drummond,Jerson G. Cadenas,Hans C. Dreyer,Yoshiaki Sato,Elena Volpi,Blake B. Rasmussen +8 more
TL;DR: Low-intensity resistance exercise training combined with blood flow restriction (REFR) increases muscle size and strength as much as conventional resistance exercise with high loads but without increasing the intensity of the exercise.
Journal ArticleDOI
HIF-1 regulation: not so easy come, easy go
TL;DR: The Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the cellular response to hypoxia and its expression levels are tightly controlled through synthesis and degradation.
Journal ArticleDOI
Induction of HIF‐1α expression by intermittent hypoxia: Involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR
TL;DR: It is demonstrated that ROS‐dependent Ca2+ signaling pathways involving phospholipase Cγ (PLCγ) and protein kinase C activation are required for IH‐evoked HIF‐1α accumulation and mTOR‐dependent protein synthesis is required for the persistent elevation of HIF-1α levels during re‐oxygenation.
References
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Journal ArticleDOI
Upstream and downstream of mTOR
Nissim Hay,Nahum Sonenberg +1 more
TL;DR: Both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis are described.
Journal ArticleDOI
eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation
TL;DR: The recent determination of the structure of eIF4E at atomic resolution has provided insight about how translation is initiated and regulated and suggests that eif4F is also implicated in malignancy and apoptosis.
Journal ArticleDOI
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
James Brugarolas,Kui Lei,Rebecca L. Hurley,Brendan D. Manning,Jan H. Reiling,Ernst Hafen,Lee A. Witters,Leif W. Ellisen,William G. Kaelin,William G. Kaelin +9 more
TL;DR: It is shown that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the Hypoxia-inducible gene REDD1/RTP801 to be inhibited, and that down-regulation of mTOR activity by hyp oxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxIA-Inducible REDD 1 gene.
Journal ArticleDOI
HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression
TL;DR: It is demonstrated that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1α protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT, and the downstream kinase FRAP.
Journal ArticleDOI
Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin
Christine C. Hudson,Mei Liu,Gary G. Chiang,Diane M. Otterness,Dawn C. Loomis,Fiona Kaper,Amato J. Giaccia,Robert T. Abraham +7 more
TL;DR: These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress.