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J Biol Chem, Vol. 274, Issue 38, 26776-26782, September 17, 1999
From the Centre de Biochimie-CNRS, Université de Nice, Parc
Valrose, 06108 Nice, France
In this work, we analyzed the role of the
PI3K-p70 S6 kinase (S6K) signaling cascade in the stimulation of
endothelial cell proliferation. We found that inhibitors of the p42/p44
MAPK pathway (PD98059) and the PI3K-p70 S6K pathway (wortmannin,
Ly294002, and rapamycin) all block thymidine incorporation stimulated
by fetal calf serum in the resting mouse endothelial cell line 1G11. The action of rapamycin can be generalized, since it completely inhibits the mitogenic effect of fetal calf serum in primary
endothelial cell cultures (human umbilical vein endothelial cells) and
another established capillary endothelial cell line (LIBE cells). The inhibitory effect of rapamycin is only observed when the inhibitor is
added at the early stages of G0-G1
progression, suggesting an inhibitory action early in G1.
Rapamycin completely inhibits growth factor stimulation of protein
synthesis, which perfectly correlates with the inhibition of cell
proliferation. In accordance with its inhibitory action on protein
synthesis, activation of cyclin D1 and p21 proteins by growth factors
is also blocked by preincubation with rapamycin. Expression of a p70
S6K mutant partially resistant to rapamycin reverses the inhibitory
effect of the drug on DNA synthesis, indicating that rapamycin action
is via p70 S6K. Thus, in vascular endothelial cells, activation of
protein synthesis via p70 S6K is an essential step for cell cycle
progression in response to growth factors.
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