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J. Biol. Chem., Vol. 276, Issue 28, 26180-26188, July 13, 2001
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From the Department of Cell Biology, The Lerner Research Institute,
The Cleveland Clinic Foundation, Cleveland, Ohio 44195
Lithium affects development of various organisms
and cell fate through the inhibition of glycogen synthase kinase-3
Lithium Inhibits Cell Cycle Progression and
Induces Stabilization of p53 in Bovine Aortic Endothelial Cells*
,
and induction of the Wnt/-catenin signaling pathway. In this study,
we investigated the effects of lithium on primary bovine aortic
endothelial cells (BAEC). Lithium treatment of BAEC induced -catenin
stabilization but failed to activate the transcriptional activity of
the -catenin/T-cell factor complex. Lithium caused a sustained
G2/M cell cycle arrest without affecting cell
viability. Reversibility of this cell cycle arrest occurred up to 3 days after treatment but was reduced thereafter. Lithium-treated BAEC
exhibited a senescent-like morphology with an increase in cells
positive for the senescence-associated--galactosidase activity.
Lithium also increased the expression of p21Cip, a
cyclin-dependent kinase inhibitor, both at the protein and RNA levels. No change in p21Cip mRNA stability was
observed, whereas the transcriptional activity of a p21Cip
promoter-luciferase construct containing p53 binding sites was increased after lithium treatment. Furthermore, lithium caused increased transcription of a reporter gene under the control of a
promoter containing the p53 consensus binding sites both in transiently
transfected BAEC and in a stably transfected fibroblast cell line.
Lithium caused accumulation of p53 protein in BAEC without affecting
p53 mRNA levels. Finally, up-regulation of p21Cip in
response to lithium did not occur in mouse embryonic fibroblasts that
were null for p53 alleles, confirming the dependence on a p53 pathway
for this lithium effect. These findings demonstrate for the first time
that lithium induces also stabilization of the tumor suppressor p53 and
reveal a new mechanism that may contribute to the neuroprotective
effects of lithium.
*
This work was supported by National Institutes of Health
Grants HL29582 and HL34727 (to P. E. D.) and by American Cancer
Society Institutional Research Grant IRG91-023-07 (to C. D. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular
Cardiology, NB50, The Lerner Research Institute, The Cleveland Clinic
Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-4673;
Fax: 216-444-9263; E-mail: maoc@ccf.org.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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