School of Chinese Medicine
Selective G2/M arrest in a p53Val135-transformed cell line induced by lithium is mediated through an intricate network of MAPK and β-catenin signaling pathways
Aims: 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). Main 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. Key findings: 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. Significance: 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. © 2012 Elsevier Inc.
β-catenin, G2/M arrest, Lithium, MAPK, p53
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Tsui, Marco Man Kin, William Chi Shing Tai, Wing Yan Wong, and Wen Luan Wendy Hsiao. "Selective G2/M arrest in a p53Val135-transformed cell line induced by lithium is mediated through an intricate network of MAPK and β-catenin signaling pathways." Life Sciences 91.10-9 (2012): 312-321.