Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner
| Autor: | Stephen N. Jones, Yifat Iluz, Elad Cohen, Judith Kasir, Rajini Mudhasani, Ola Larsson, Markus A. Rüegg, Oded Meyuhas, Arjuna Rajakumar, Ivan Topisirovic, Nadine Cybulski, Rachel Miloslavski, Zvi Hayouka, Valentina Gandin, Adam Avraham |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Regulator
Cell Cycle Proteins RNA 5' Terminal Oligopyrimidine Sequence Tuberous Sclerosis Complex 1 Protein Stress Physiological Tuberous Sclerosis Complex 2 Protein Genetics Protein biosynthesis Humans Amino Acids Cyclin D3 Eukaryotic Initiation Factors Phosphorylation Molecular Biology Psychological repression PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Monomeric GTP-Binding Proteins biology TOR Serine-Threonine Kinases Tumor Suppressor Proteins Translation (biology) Cell Biology General Medicine Articles Regulatory-Associated Protein of mTOR Phosphoproteins Molecular biology Oxygen HEK293 Cells Rapamycin-Insensitive Companion of mTOR Protein Protein Biosynthesis biology.protein Translational Activation Carrier Proteins RHEB Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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