Glycogen Synthase Kinase 3 (GSK3) Inhibitor, SB-216763, Promotes Pluripotency in Mouse Embryonic Stem Cells

Kirby, Leslie; Schott, Jason T.; Noble, Brenda L.; Mendez, Daniel C.; Caseley, Paul S.; Peterson, Sarah C.; Routledge, Tyler J.; Patel, Nilay

doi:10.1371/journal.pone.0039329

Cited by 41 publications

(30 citation statements)

References 60 publications

(120 reference statements)

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“…21 It has been reported that SB216763 (ATP-competitive), a GSK3 inhibitor, effectively activated -catenin-mediated transcription. 22 Naito et al 23 showed that GSK3 nuclear expression was associated with highgrade tumors, metastasis, and worse survival in bladder cancer patients. Dose and time-dependent SB216763 improved the cytotoxic effect against the two human urothelial carcinoma cell lines, UMUC3 and UMUC14, suggesting potential therapeutic uses for GSK3 inhibitors.…”

mentioning

confidence: 99%

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Varol

Konac

Bilen

2014

Exp Biol Med (Maywood)

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DNA methylation is considered as one of the most important epigenetic mechanisms and it is catalyzed by DNA methyltransferases (DNMTs). DNMT1 abundance has been frequently seen in urogenital system tumors but the reasons for this abundance are not well understood. We aimed to look into the effects of Wnt/b-catenin signaling pathway on overexpression of DNMT1 and aberrant expression of UHRF1 and HAUSP which are responsible for stability of DNMT1 at transcriptional and protein levels in urogenital cancers. In this context, firstly, Wnt/b-catenin signaling pathway was activated by using SB216763 which is a glycogen synthase kinase-3 (GSK3) b inhibitor. Cell proliferation levels in bladder cancer cells, renal cell carcinoma, and prostate cancer cells treated with GSK3b inhibitor (SB216763) were detected by WST-1 reagent. WIF-1 gene methylation profile was determined by methylation-specific PCR (MSP); expression levels of target genes -catenin and WIF-1 by real-time PCR; and protein levels of -catenin, DNMT1, pGSK3(Ser9), HAUSP, and UHRF1 by Western Blot. Our results indicated that treatment with SB216763 caused an increased cell proliferation at low dose. mRNA levels of -catenin increased after treatment with SB216273 and protein levels of pGSK3b(Ser9), b-catenin, and DNMT1 increased in comparison to control. HAUSP and UHRF1 were either up-regulated or down-regulated at the same doses depending on the type of cancer. Also, we showed that protein levels of DNMT1, b-catenin, HAUSP, and UHRF1 decreased after re-expression of WIF-1 following treatment with DAC. In Caki-2 cells, -catenin pathway might have accounted for the stability of DNMT1 expression, whereas such relation is not valid for T24 and PC3 cells. Our findings may offer a new approach for determination of molecular effects of Wnt/b-catenin signal pathway on DNMT1. This may allow us to identify new molecular targets for the treatment of urogenital cancers.

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confidence: 99%

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Varol

Konac

Bilen

2014

Exp Biol Med (Maywood)

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“…However, during development, GSK-3 activity enhances neuronal differentiation of radial glia and reduces progenitor expansion (Kim et al, 2009). In agreement with these observations, GSK-3 inhibitors significantly improve the reprogramming efficiency of fibroblasts towards pluripotency (Kirby et al, 2012;Lyssiotis et al, 2009) and facilitate self-renewal of mouse embryonic stem cells (Knockaert et al, 2002), probably through activation of Wnt signalling (Marson et al, 2008). These observations suggest that the downregulation of the GSK-3 pathway opposes neuronal differentiation and promotes a progenitor-like stage.…”

Section: Direct Neuronal Reprogramming: Learning From Developmentmentioning

confidence: 63%

Direct neuronal reprogramming: learning from and for development

2016

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The key signalling pathways and transcriptional programmes that instruct neuronal diversity during development have largely been identified. In this Review, we discuss how this knowledge has been used to successfully reprogramme various cell types into an amazing array of distinct types of functional neurons. We further discuss the extent to which direct neuronal reprogramming recapitulates embryonic development, and examine the particular barriers to reprogramming that may exist given a cell's unique developmental history. We conclude with a recently proposed model for cell specification called the 'Cook Islands' model, and consider whether it is a fitting model for cell specification based on recent results from the direct reprogramming field.

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“…In an attempt to expand Isl1 + cells, we induced Wnt/ β -catenin, a signaling pathway known to support self-renewal of Isl1 + cardiac cells (Figure 3(a)). When SB-216763 [29], a GSK3 inhibitor, was added at days 5–8, significant expansion of Isl1 + cells was observed at d12 (Figure 3(b)). …”

Section: Resultsmentioning

confidence: 99%

Isolation of an ES‐Derived Cardiovascular Multipotent Cell Population Based on VE‐Cadherin Promoter Activity

Maltabe

Barka

Kontonika

et al. 2016

Stem Cells International

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Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/β-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT+ (~47%) and VE-cadherin+ (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual-progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches.

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Glycogen Synthase Kinase 3 (GSK3) Inhibitor, SB-216763, Promotes Pluripotency in Mouse Embryonic Stem Cells

Cited by 41 publications

References 60 publications

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Direct neuronal reprogramming: learning from and for development

Isolation of an ES‐Derived Cardiovascular Multipotent Cell Population Based on VE‐Cadherin Promoter Activity

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