Mammalian Target of Rapamycin Is Required for Thrombopoietin-Induced Proliferation of Megakaryocyte Progenitors
- 1 January 2006
- journal article
- Published by Oxford University Press (OUP) in The International Journal of Cell Cloning
- Vol. 24 (1), 105-114
- https://doi.org/10.1634/stemcells.2005-0062
Abstract
Thrombopoietin (TPO) is a potent regulator of megakaryopoiesis and stimulates megakaryocyte (MK) progenitor expansion and MK differentiation. In this study, we show that TPO induces activation of the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in translational regulation and is required for proliferation of MO7e cells and primary human MK progenitors. Treatment of MO7e cells, human CD34+, and primary MK cells with the mTOR inhibitor rapamycin inhibits TPO-induced cell cycling by reducing cells in S phase and blocking cells in G0/G1. Rapamycin markedly inhibits the clonogenic growth of MK progenitors with high proliferative capacity but does not reduce the formation of small MK colonies. Addition of rapamycin to MK suspension cultures reduces the number of MK cells, but inhibition of mTOR does not significantly affect expression of glycoproteins IIb/IIIa (CD41) and glycoprotein Ib (CD42), nuclear polyploidization levels, cell size, or cell survival. The downstream effectors of mTOR, p70 S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1), are phosphorylated by TPO in a rapamycin- and LY294002-sensitive manner. Part of the effect of the phosphatidyl inositol 3-kinase pathway in regulating megakaryopoiesis may be mediated by the mTOR/S6K/4E-BP1 pathway. In conclusion, these data demonstrate that the mTOR pathway is activated by TPO and plays a critical role in regulating proliferation of MK progenitors, without affecting differentiation or cell survival.Keywords
This publication has 28 references indexed in Scilit:
- Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitiveNature, 2004
- Upstream and downstream of mTORGenes & Development, 2004
- TOR signalling in bugs, brain and brawnNature Reviews Molecular Cell Biology, 2003
- Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR ActionCell, 2002
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002
- Forkhead Family Transcription Factor FKHRL1 Is Expressed in Human MegakaryocytesJournal of Biological Chemistry, 2001
- c-Mpl ligand is a humoral regulator of megakaryocytopoiesisNature, 1994
- Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietinNature, 1994
- Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivoNature, 1994
- Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligandNature, 1994