Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner
Authors
Miloslavski, RachelCohen, Elad
Avraham, Adam
Iluz, Yifat
Hayouka, Zvi
Kasir, Judith
Mudhasani, Rajini R.
Jones, Stephen N.
Cybulski, Nadine
Ruegg, Markus A.
Larsson, Ola
Gandin, Valentina
Rajakumar, Arjuna
Topisirovic, Ivan
Meyuhas, Oded
UMass Chan Affiliations
Department of Cell and Developmental BiologyDocument Type
Journal ArticlePublication Date
2014-06-01
Metadata
Show full item recordAbstract
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. of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.Source
Miloslavski R, Cohen E, Avraham A, Iluz Y, Hayouka Z, Kasir J, Mudhasani R, Jones SN, Cybulski N, Rüegg MA, Larsson O, Gandin V, Rajakumar A, Topisirovic I, Meyuhas O. Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner. J Mol Cell Biol. 2014 Jun;6(3):255-66. doi: 10.1093/jmcb/mju008. Link to article on publisher's siteDOI
10.1093/jmcb/mju008Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36024Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1093/jmcb/mju008