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Browsing by Author "Ragoussis, Jiannis"
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Item MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU(Public Library of Science, 2010-04-26) Favaro, Elena; Ramachandran, Anassuya; McCormick, Robert; Gee, Harriet; Blancher, Christine; Crosby, Meredith; Devlin, Cecilia; Blick, Christopher; Buffa, Francesca; Li, Ji-Liang; Vojnovic, Borivoj; Neves, Ricardo Pires das; Glazer, Peter; Iborra, Francisco; Ivan, Mircea; Ragoussis, Jiannis; Harris, Adrian L.; Medicine, School of MedicineHypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis. Methods and Findings In human cancer cell lines and tumours, we found that miR-210 targets the mitochondrial iron sulfur scaffold protein ISCU, required for assembly of iron-sulfur clusters, cofactors for key enzymes involved in the Krebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygen species (ROS) in hypoxia. ISCU suppression reduced mitochondrial complex 1 activity and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. Cancers with low ISCU had a worse prognosis. Conclusions Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.Item Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS(Nature Publishing Group, 2020-09-21) Wu, Xue; Niculite, Cristina M.; Preda, Mihai Bogdan; Rossi, Annalisa; Tebaldi, Toma; Butoi, Elena; White, Mattie K.; Tudoran, Oana M.; Petrusca, Daniela N.; Jannasch, Amber S.; Bone, William P.; Zong, Xingyue; Fang, Fang; Burlacu, Alexandrina; Paulsen, Michelle T.; Hancock, Brad A.; Sandusky, George E.; Mitra, Sumegha; Fishel, Melissa L.; Buechlein, Aaron; Ivan, Cristina; Oikonomopoulos, Spyros; Gorospe, Myriam; Mosley, Amber; Radovich, Milan; Davé, Utpal P.; Ragoussis, Jiannis; Nephew, Kenneth P.; Mari, Bernard; McIntyre, Alan; Konig, Heiko; Ljungman, Mats; Cousminer, Diana L.; Macchi, Paolo; Ivan, Mircea; Medicine, School of MedicineWe hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.