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Lithium Inhibits Ceramide- and Etoposide-Induced Protein Phosphatase 2A Methylation, Bcl-2 Dephosphorylation, Caspase-2 Activation, and Apoptosis

Institute of Basic Medical Sciences (C.-L.C.), Department of Microbiology and Immunology (C.-F.L., Y.-S.L.), and Institute of Molecular Medicine (C.-W.C.), National Cheng Kung University Medical College, Tainan, Taiwan; Department of Microbiology and Immunology, Chung-Shan Medical University, Taichung, Taiwan (M.-S.J.); and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan (C.-W.C., Y.-S.L.)

Lithium confers cell protection against stress and toxic stimuli. Although lithium inhibits a number of enzymes, the antiapoptotic mechanisms of lithium remain unresolved. Here, we report a novel role of lithium on the blockage of ceramide- and etoposide-induced apoptosis via inhibition of protein phosphatase 2A (PP2A) activity. Overexpression of PP2A resulted in caspase-2 activation, mitochondrial damage, and cell apoptosis that were inhibited by okadaic acid (OA) and lithium. Lithium and OA abrogated ceramide- and etoposide-induced Bcl-2 dephosphorylation at serine 70. Furthermore, ceramide- and etoposide-induced PP2A activation involved methylation of PP2A C subunit, which lithium suppressed. Lithium caused dissociation of PP2A B subunit from the PP2A core enzyme, whereas ceramide caused recruitment of the B subunit. Taken together, lithium exhibited an antiapoptotic effect by inhibiting Bcl-2 dephosphorylation and caspase-2 activation, which involved, at least in part, a mechanism of down-regulating PP2A methylation and PP2A activity.

Address correspondence to: Dr. Yee-Shin Lin, Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701, Taiwan. E-mail: yslin1{at}mail.ncku.edu.tw

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