Abstract
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.
Footnotes
-
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
-
This work was supported by the Leukaemia and Lymphoma Research Fund [Grant 08046] and the Wellcome Trust [Grant 074452].
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.064055.
-
ABBREVIATIONS:
- mTOR
- mammalian target of rapamycin
- GAS5
- growth-arrest-specific transcript 5
- FKBP38
- 38-kDa FK506 binding protein
- FKBP12
- 12-kDa FK506-binding protein
- 4E-BP1
- eukaryotic translation initiation factor 4E binding protein 1
- 5′TOP
- 5′ terminal oligopyrimidine
- PHA
- phytohemagglutinin
- BrdU
- 5-bromo 2′-deoxyuridine
- siRNA
- small interfering RNA
- PBS
- phosphate-buffered saline
- PI
- propidium iodide
- ELISA
- enzyme-linked immunosorbent assay.
- Received February 10, 2010.
- Accepted April 26, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|