title: Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner.
abstract: Cells encountering hypoxic stress conserve resources and energy by downregulating the protein synthesis. Here we demonstrate that one mechanism in this response is the translational repression of TOP mRNAs that encode components of the translational apparatus. This mode of regulation involves TSC and Rheb, as knockout of TSC1 or TSC2 or overexpression of Rheb rescued TOP mRNA translation in oxygen-deprived cells. Stress-induced translational repression of these mRNAs closely correlates with the hypophosphorylated state of 4E-BP, a translational repressor. However, a series of 4E-BP loss- and gain-of-function experiments disprove a cause-and-effect relationship between the phosphorylation status of 4E-BP and the translational repression of TOP mRNAs under oxygen or growth factor deprivation. Furthermore, the repressive effect of anoxia is similar to that attained by the very efficient inhibition of mTOR activity by Torin 1, but much more pronounced than raptor or rictor knockout. Likewise, deficiency of raptor or rictor, even though it mildly downregulated basal translation efficiency of TOP mRNAs, failed to suppress the oxygen-mediated translational activation of TOP mRNAs. Finally, co-knockdown of TIA-1 and TIAR, two RNA-binding proteins previously implicated in translational repression of TOP mRNAs in amino acid-starved cells, failed to relieve TOP mRNA translation under other stress conditions. Thus, the nature of the proximal translational regulator of TOP mRNAs remains elusive.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Miloslavski
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel Present address: Migal-Galilee Research Institute, Kiryat Shmona 11016, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Cohen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Adam
authors.initials: A
authors.lastname: Avraham
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Iluz
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Judith
authors.initials: J
authors.lastname: Kasir
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, North Worcester, MA 01655, USA Present address: United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
authors.forename: Rajini
authors.initials: R
authors.lastname: Mudhasani
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, North Worcester, MA 01655, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland Present address: ADAM, Montreal, QC H3N 2C7, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Cybulski
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm SE-171 76, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and Department of Oncology, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and Department of Oncology, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Arjuna
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and Department of Oncology, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel meyuhas@cc.huji.ac.il.
authors.forename: Oded
authors.initials: O
authors.lastname: Meyuhas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000172:deficiency / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D056743:Cyclin D3 / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D057809:HEK293 Cells; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D038641:RNA 5' Terminal Oligopyrimidine Sequence / Q000235:genetics*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056743:Cyclin D3; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C525637:rictor protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D010100:Oxygen
keywords: 4E-BP; TOP mRNAs; hypoxia; mTOR; translational control