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.
journal_name
J Mol Cell Bioljournal_title
Journal of molecular cell biologyauthors
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 Odoi
10.1093/jmcb/mju008subject
Has Abstractpub_date
2014-06-01 00:00:00pages
255-66issue
3eissn
1674-2788issn
1759-4685pii
mju008journal_volume
6pub_type
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