Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors

Sinha, Diviya; Wang, Zhiyong; Ruchalski, Kathleen; Levine, Jerrold S.; Krishnan, Sadagopan; Lieberthal, Wilfred; Schwartz, John H.; Borkan, Steven C.

doi:10.1152/ajprenal.00189.2004

Cited by 111 publications

(107 citation statements)

References 75 publications

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“…As shown in Fig. 7a, both LiCl and BIO significantly increased the number of viable WT cells in 48 h, as reported by others (19,28,31). As expected, targeted mutation of Epm2a also increased cell growth.…”

Section: Gsk-3␤supporting

confidence: 88%

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Laforin Negatively Regulates Cell Cycle Progression through Glycogen Synthase Kinase 3β-Dependent Mechanisms

Liu

Wang²,

Chen³

et al. 2008

Molecular and Cellular Biology

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Glycogen synthase kinase 3␤ (GSK-3␤) represses cell cycle progression by directly phosphorylating cyclin D1 and indirectly regulating cyclin D1 transcription by inhibiting Wnt signaling. Recently, we reported that the Epm2a-encoded laforin is a GSK-3␤ phosphatase and a tumor suppressor. The cellular mechanism for its tumor suppression remains unknown. Using ex vivo thymocytes and primary embryonic fibroblasts from Epm2a ؊/؊ mice, we show here a general function of laforin in the cell cycle regulation and repression of cyclin D1 expression. Moreover, targeted mutation of Epm2a increased the phosphorylation of Ser9 on GSK-3␤ while having no effect on the phosphorylation of Ser21 on GSK-3␣. In the GSK-3␤ ؉/؉ but not the GSK-3␤ ؊/؊ cells, Epm2a small interfering RNA significantly enhanced cell growth. Consistent with an increased level of cyclin D1, the phosphorylation of retinoblastoma protein (Rb) and the levels of Rb-E2F-regulated genes cyclin A, cyclin E, MCM3, and PCNA are also elevated. Inhibitors of GSK-3␤ selectively increased the cell growth of Epm2a ؉/؉ but not of Epm2a ؊/؊ cells. Taken together, our data demonstrate that laforin is a selective phosphatase for GSK-3␤ and regulates cell cycle progression by GSK-3␤-dependent mechanisms. These data provide a cellular basis for the tumor suppression activity of laforin.Cell cycle progression is facilitated by cyclin-dependent kinases (CDKs) that are activated by cyclins, including cyclin D1, and inhibited by CDK inhibitors (27,29). Cyclin D1 is a critical regulator involved in cell cycle progression through the G 1 phase and into the S phase (18, 33). The active cyclin D1/ CDK4 complex initiates the phosphorylation of retinoblastoma protein (Rb) (9), which disrupts Rb-mediated transcriptional repression of E2F and facilitates cell cycle progression (27,29). However, the activity of cyclin D1/CDK4 is specifically inhibited by four INK4 proteins (p 16INK4a , p 15INK4b , p 18INK4c , and p 19INK4d ) (13,14,34) and by glycogen synthase kinase 3␤ (GSK-3␤) (3, 7). GSK-3␤ phosphorylates cyclin D1 at Thr286 (3, 7) and thereby triggers its nuclear export, ubiquitination, and proteasomal degradation (7).GSK-3␤ is a multifunctional serine/threonine protein kinase (2, 6, 12) and a component of multiple signal transduction pathways, including the insulin, Wnt, and Ras signaling pathways. In the Wnt signaling pathway, GSK-3␤ phosphorylates ␤-catenin for its degradation and is an essential negative regulator of the Wnt/␤-catenin pathway (1, 4). Wnt inhibits the enzymatic activity of GSK-3␤, thereby stabilizing ␤-catenin and enabling its association with T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) protein complexes to activate the transcription of target genes, including those like c-myc and cyclin D1 (25). However, how GSK-3␤ activity is regulated has been poorly understood.Epm2a encodes a 331-amino-acid dual-specificity phosphatase called laforin (5,10,(20)(21)(22). Loss-of-function mutations in Epm2a result in Lafora disease, an autosomal recessive disorder i...

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Section: Gsk-3␤supporting

confidence: 88%

“…Previous studies have demonstrated that GSK-3␤ inhibitors promote cell cycle progression and increase its phosphorylation (19,28,31). Since the Epm2a mutation has the same effect, it is of great interest to determine if the underlying mechanism is the same.…”

Section: Gsk-3␤mentioning

confidence: 99%

Laforin Negatively Regulates Cell Cycle Progression through Glycogen Synthase Kinase 3β-Dependent Mechanisms

Liu

Wang²,

Chen³

et al. 2008

Molecular and Cellular Biology

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“…Instead, several GSK3-specific inhibitors other than lithium, like TDZD-8 or BIO, mimicked the protective effects of lithium. 12,15,16,18,[87][88][89] Consistently, mice carrying an inactive GSK3b mutant were protected from mercuric chloride-induced nephrotoxic injury. 90 Therefore, we will focus on GSK3 as the target of lithium contributing to renoprotection with lithium ( Figure 2).…”

Section: Molecular Mechanisms Of the Renoprotective Effects Of Lithiummentioning

confidence: 83%

“…18,90 This increased capacity might be caused by an enhanced b-catenin-mediated transcription of proliferative genes (canonical Wnt signaling), because this pathway was also activated in cultured mouse proximal tubular cells treated with lithium and the GSK3 inhibitor BIO. 89 Although canonical Wnt signaling is essential for self-repair during AKI, 91 it is less evident whether pharmacologic repair by lithium also requires canonical Wnt signaling. In fact, the lower lithium amounts used in the AKI mice barely affected canonical Wnt signaling, whereas the expression of proliferative proteins, such as cyclinD1, c-Myc, and HIF-1a, were increased.…”

Section: Gsk3 Inhibition Allows Cell Repair By Activating Proprolifermentioning

confidence: 99%

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

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Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for .60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

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“…Intensive apoptosis was observed when renal proximal tubular cells were cultured in the absence of growth factors [44]. The authors studied the possibility of enhancing cell survival under these conditions by activating Wntdependent signaling pathway via GSK3 inhibition by, in particular, lithium.…”

Section: Abstract: Lithium Glycogen Synthase Kinase 3 β-Amylmentioning

confidence: 99%