Cd. Mao et al., Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells, J BIOL CHEM, 276(28), 2001, pp. 26180-26188
Lithium affects development of various organisms and cell fate through the
inhibition of glycogen synthase kinase-3 beta and induction of the Wnt/beta
-catenin signaling pathway. In this study, we investigated the effects of
lithium on primary bovine aortic endothelial cells (BAEC), Lithium treatmen
t of BAEC induced beta -catenin stabilization but failed to activate the tr
anscriptional activity of the beta -catenin/T-cell factor complex. Lithium
caused a sustained G(2)/M cell cycle arrest without affecting cell viabilit
y. Reversibility of this cell cycle arrest occurred up to 3 days after trea
tment but was reduced thereafter. Lithium-treated BAEC exhibited a senescen
t-like morphology with an increase in cells positive for the senescence-ass
ociated-beta -galactosidase activity. Lithium also increased the expression
of p21(CiP), a cyclin-dependent kinase inhibitor, both at the protein and
RNA levels. No change in p21(Cip) mRNA stability was observed, whereas the
transcriptional activity of a p21(Cip) promoter-luciferase construct contai
ning 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 transient
ly transfected BAEC and in a stably transfected fibroblast cell line. Lithi
um caused accumulation of p53 protein in BAEC without affecting p53 mRNA le
vels. Finally, upregulation of p21(Cip) in response to lithium did not occu
r in mouse embryonic fibroblasts that were null for p53 alleles, confirming
the dependence on a p53 pathway for this lithium effect. These findings de
monstrate 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.