PI3-KINASE INHIBITORS LY294002 AND WORTMANNIN HAVE DIFFERENT EFFECTS ON PROLIFERATION OF MURINE EMBRYONIC STEM
CELLS
M. S. Lianguzova,1,* I. A. Chuykin,1 A. Nordheim,2
V. A. Pospelov 1
1 Institute of Cytology RAS, St. Petersburg, Russia, and
2 Tuebingen University, Tuebingen, Germany;
* e-mail: lianguzova@gmail.com
Murine embryonic stem (mES) cells can proliferate independently of the presence of growth factors in the medium.
It is yet unknown what intrinsic activity triggers cell cycle events in mES cells. Here we investigated the
contribution of the PI3-kinase cascade to autonomous proliferation of mES cell using PI3-kinase inhibitors
wortmannin and LY294002. Wortmannin displays a weaker inhibitory effect on phosphorylation of PI3-kinase pathway
target PKB as compared with LY294002, and does not downregulate mES cells proliferation, while LY294002 causes a
strong decrease in the share of cells in S-phase and accumulation of cells in G1 phase. Both inhibitors
cause significant decrease in cyclin D1 amount. The treatment with LY294002, rather than with wortmannin results in a
decrease of cyclin E amount and cyclin E-assossiated kinase activity. In mES cells, inactivation of
PI3-kinase-dependent pathway and G1 arrest are not accompanied by induction of p27kip 1
transcription and accumulation of this inhibitor of cyclin-cdk complexes at the protein level, implying that these
events accomplished by some p27kip 1-independent mechanism. Both LY294002 and wortmannin cause apoptotic
death of mES cells and downregulate the growth of population. Thus, inactivation of PI3-kinase in mES cells may lead
to apoptosis rather than to cell cycle arrest.
Key words: murine embryonic stem cells, proliferation, PI3-kinase, LY294002, wortmannin
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