RT Journal Article
SR Electronic
T1 Inhibition of Human T-Cell Proliferation by Mammalian Target of Rapamycin (mTOR) Antagonists Requires Noncoding RNA Growth-Arrest-Specific Transcript 5 (GAS5)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 19
OP 28
DO 10.1124/mol.110.064055
VO 78
IS 1
A1 Mirna Mourtada-Maarabouni
A1 Anwar M. Hasan
A1 Farzin Farzaneh
A1 Gwyn T. Williams
YR 2010
UL http://molpharm.aspetjournals.org/content/78/1/19.abstract
AB The central importance of the serine/threonine protein kinase mTOR (mammalian Target of Rapamycin) in the control of cell growth and proliferation is well established. However, our knowledge both of the upstream pathways controlling mTOR activity and of the downstream events mediating these effects is still seriously incomplete. We report a previously unsuspected role for the nonprotein-coding RNA GAS5 in the inhibition of T-cell proliferation produced by mTOR antagonists such as rapamycin. GAS5 transcripts are up-regulated during growth arrest and after rapamycin treatment, and GAS5 has recently been shown to be necessary and sufficient for normal T-cell growth arrest. Down-regulation of GAS5 using RNA interference protects both leukemic and primary human T cells from the inhibition of proliferation produced by mTOR antagonists. The GAS5 transcript is a member of the 5′ terminal oligopyrimidine class of RNAs, which is specifically controlled at the level of translation by the mTOR pathway, and the effects of GAS5 on the cell cycle provide a novel and important link to the control of proliferation. These observations point to a significant advance in our understanding of the mechanism of action of mTOR inhibitors, which is likely to lead to improvements in immunosuppressive and cancer therapy.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics