Lithium Inhibits Cell Cycle Progression and Induces Stabilization of p53 in Bovine Aortic Endothelial Cells

Abstract

Lithium affects development of various organisms and cell fate through the inhibition of glycogen synthase kinase-3␤ 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 G 2 /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 cyclindependent 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, upregulation 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.

Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation

“…Considerable evidence from previous reports has established that VEGF signaling through Flk-1/KDR/ VEGFR-2 or Flt-1/VEGFR1 induces activation of ERK1/2, p38 MAPK, Akt, phospholipase Cg, and focal adhesion kinase (Abedi and Zachary, 1997;Gerber et al, 1998b;Kroll and Waltenberger, 1997;Mao et al, 2001;Wu et al, 2000). While focal adhesion kinase is associated with cell migration (Lu (Parrizas et al, 1997).…”

Lithium inhibits proliferation of human esophageal cancer cell line Eca-109 by inducing a G2/M cell cycle arrest

“…Analysis of cell cycle distribution showing an increase of cells in G 2 /M phase and a decrease in G 0 /G 1 phase indicated that lithium could lead to a G 2 /M cell cycle arrest ( Figure 3 and Table 1), which is the common characteristic of cell cycle arrest induced by lithium. However, different cell types have their own doses of sensitivity [15,17] . In the report of Mao et al [17] , 5 mmol/L lithium was enough to induce a G 2 /M phase arrest of bovine aortic endothelial cells.…”

“…Lithium has been shown to be a specific and noncompetitive inhibitor of GSK-3β activity in vitro [8,9] and in vivo [10] . It has been proved that lithium could promote [11][12][13][14] or inhibit [7,[15][16][17] cell cycle transition and proliferation of some primary cultures or cell lines by inhibiting GSK-3β, depending on the cell type. However, whether lithium influences the growth and proliferation of EC cells remains unknown to date.…”

Glycogen Synthase Kinase-3 Couples AKT-dependent Signaling to the Regulation of p21Cip1 Degradation

“…Thereby, a concept of phosphorylationdependent regulation of p21 Cip1 turnover resembles the mechanism by which GSK-3-mediated phosphorylation triggers both nuclear exit and subsequently the ubiquitin-mediated proteasomal degradation of another regulator of G 1 cell cycle progression, cyclin D (13,25). While preparing this manuscript, Mao et al (26) published that LiCl stabilized p53 and thereby transcriptionally increased p21…”