title: 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 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.
authors.affiliation: Department of Cell Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. maoc@ccf.org
authors.forename: C D
authors.initials: CD
authors.lastname: Mao
authors.forename: P
authors.initials: P
authors.lastname: Hoang
authors.forename: P E
authors.initials: PE
authors.lastname: DiCorleto
mesh_terms: 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
chemical_list: D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D008094:Lithium