PMID- 16123382
OWN - NLM
STAT- MEDLINE
DCOM- 20060609
LR  - 20131121
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 24
IP  - 1
DP  - 2006 Jan
TI  - Mammalian target of rapamycin is required for thrombopoietin-induced 
      proliferation of megakaryocyte progenitors.
PG  - 105-14
AB  - 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.
FAU - Drayer, A Lyndsay
AU  - Drayer AL
AD  - Department of Research and Education, Sanquin Blood Bank, North East Region, P.O. 
      Box 1191, 9701 BD, Groningen, The Netherlands. L.drayer@sanquin.nl
FAU - Olthof, Sandra G M
AU  - Olthof SG
FAU - Vellenga, Edo
AU  - Vellenga E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050825
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Antigens, CD34)
RN  - 9014-42-0 (Thrombopoietin)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antigens, CD34/metabolism
MH  - Cell Cycle/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Humans
MH  - Megakaryocytes/*physiology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - Stem Cells/*physiology
MH  - Thrombopoietin/*pharmacology
EDAT- 2005/08/27 09:00
MHDA- 2006/06/10 09:00
CRDT- 2005/08/27 09:00
PHST- 2005/08/27 09:00 [pubmed]
PHST- 2006/06/10 09:00 [medline]
PHST- 2005/08/27 09:00 [entrez]
AID - 2005-0062 [pii]
AID - 10.1634/stemcells.2005-0062 [doi]
PST - ppublish
SO  - Stem Cells. 2006 Jan;24(1):105-14. doi: 10.1634/stemcells.2005-0062. Epub 2005 
      Aug 25.