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Life Sci. 2012 Sep 24;91(9-10):312-21. doi: 10.1016/j.lfs.2012.07.027. Epub 2012 Aug 1.

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.

Author information

1
Center for Inflammatory and Cancer Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China.

Abstract

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.

PMID:
22884810
DOI:
10.1016/j.lfs.2012.07.027
[Indexed for MEDLINE]

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