title: Selective G2/M arrest in a p53(Val135)-transformed cell line induced by lithium is mediated through an intricate network of MAPK and β-catenin signaling pathways.
abstract: OBJECTIVE
  Lithium is a common mood stabilizer to treat bipolar disorder. It has a narrow window of therapeutic action and its mechanism of action and possible side effects are still not fully understood. Lithium is a potent inhibitor of glycogen synthase kinase 3β (GSK-3β). Previous studies indicated that lithium can induce cell cycle arrest by stabilization of p53. In order to further elucidate the signaling mechanism of lithium-induced cell cycle arrest and its potential pharmacological effect on p53 transformed cell lines, we studied the effect of lithium on the rat fibroblast cell line R6 and a p53(Val135) transformed cell line R6T2 (hereafter referred to as T2).
  
  
  METHODS
  We monitored the effects of lithium on cell cycle progression by FACS analysis and the activation of MAPK signaling pathways by Western blot using anti-phospho-MAPK antibodies in R6 and T2.
  
  
  RESULTS
  We report here lithium can induce G2/M arrest in T2 independent of β-catenin signals. Lithium increases phosphorylation of extracellular signal-regulated kinases (ERKs) leading to the up-regulation of p53 levels and subsequent G2/M arrest. Lithium also induced phosphorylation of p38 MAPK, consequently downregulated p53 and alleviated G2/M cell cycle arrest. We further showed the gate-keeping role of p53 in the lithium-induced G2/M arrest in the T2 cell line.
  
  
  CONCLUSIONS
  Our results reveal a novel mechanism underlying the differential response of the transformed and normal R6 to lithium-induced G2/M cell cycle arrest and delineate the multiplicity of signaling pathways dictating the cell fate in responding to cell stress signals.
authors.affiliation: Center for Inflammatory and Cancer Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China.
authors.forename: Marco Man Kin
authors.initials: MM
authors.lastname: Tsui
authors.forename: William Chi Shing
authors.initials: WC
authors.lastname: Tai
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: Wong
authors.forename: Wen Luan Wendy
authors.initials: WL
authors.lastname: Hsiao
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018692:Antimanic Agents; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; D018021:Lithium Chloride