Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells.
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 treatment of BAEC induced beta-catenin stabilization but failed to activate the transcriptional activity of the beta-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-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 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 p21(Cip) 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.
Mao
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Department of Cell Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. maoc@ccf.org
Hoang
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DiCorleto
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PE
D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D008094:Lithium / Q000494:pharmacology*; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin
D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D008094:Lithium