title: A critical role for mTORC1 in erythropoiesis and anemia.
abstract: Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link the nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation and establish that perturbations in this pathway result in anemia.
authors.affiliation: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.affiliation: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Schmidt
authors.affiliation: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Kivanc
authors.initials: K
authors.lastname: Birsoy
authors.affiliation: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Tan
authors.affiliation: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism; D000328:Adult; D000740:Anemia / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004920:Erythropoiesis / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D007501:Iron / Q000494:pharmacology; D020014:K562 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000076223:Regulatory-Associated Protein of mTOR; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D007501:Iron; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: RBC; anemia; cell biology; erythropoiesis; human biology; mTOR; mTORC1; medicine; mouse