Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor

Satô, Noboru; Meijer, Laurent; Skaltsounis, Léandros; Greengard, Paul; Brivanlou, Ali H.

doi:10.1038/nm979

Cited by 1,895 publications

(1,775 citation statements)

References 46 publications

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“…Additionally, b-catenin activity is capable of maintaining an undifferentiated state in teratomas, implying that b-catenin signaling may push germ cells towards a proliferative undifferentiated state (Kielman et al, 2002). This finding agrees with the work of many studies that uncovered a role for b-catenin in stem cell maintenance (Li et al, 2003;Willert et al, 2003;Liu et al, 2004;Sato et al, 2004).…”

Section: Discussionsupporting

confidence: 86%

“…In the hematopoietic system, Wnt/ b-catenin signaling maintains cells in a pluripotent proliferative state (Willert et al, 2003). Similar findings were found in human embryonic stem cells where inhibition of GSK3b and subsequent b-catenin stabilization maintained the pluripotency of the cells in culture (Sato et al, 2004). During Wnt-induced transformation of mammary tissue this link to stem cell renewal is thought to result in preferential accumulation and induction of cancer from mammary progenitor cells (Li et al, 2003).…”

supporting

confidence: 52%

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P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

2006

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b-catenin, an oncogene, and P53, a tumor suppressor, are common targets of mutation in human cancers. It has been observed that P53 is often inactivated in tumors involving b-catenin activation. In an attempt to model this situation in vivo, we crossed the previously characterized MMTV-DN-b-catenin mouse with the P53 knockout mouse. Female multiparous mice that carry the MMTV-DN-bcatenin transgene and that are heterozygous for P53 (Tg DN-bCat / þ , P53 þ /À) display an increased tumor burden (2.05 vs 1.31 tumors/animal), with a generally more advanced pathology, and increased metastatic rate (39 vs 0%) relative to transgenic female mice that are wild type for P53 (Tg DN-bCat / þ , P53 þ / þ ). These differences were not due to complete loss of P53 as only one of 21 tumors demonstrated loss of heterozygosity at the P53 locus. Furthermore, no mutations were present in tumors retaining a single wild-type allele. Tg DN-bCat / þ , P53À/À male mice developed testicular teratomas and survived an average of 65 days, whereas non-Tg DN-bCat , P53À/À males survived an average of 84 days. Sixty-two percent of Tg DN-bCat , P53À/À mice developed testicular teratomas, whereas only 10% of the non-Tg DN-bCat , P53À/À mice developed these tumors. These results indicate that the level of P53 and the tissue of origin are important factors in determining outcome of cancer caused by oncogene activation.

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Section: Discussionsupporting

confidence: 86%

supporting

confidence: 52%

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

2006

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“…GSK-3b inhibition through BIO is of particular clinical interest, as the effects can preserve and support proliferation of normal hematopoietic stem cells through canonical WNT signaling (Sato et al, 2004). In contrast, GSK-3b inhibition by BIO suppressed proliferation of various leukemia cell lines, including K562 (Holmes et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were coexpressed in 80% of AML (n ¼ 30) and 40% in T-ALL (n ¼ 30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were costimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

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“…6A, 6B). However, previous reports have also shown that b-catenin/Wnt signaling in undifferentiated ESCs can maintain pluripotency [37,41,42], implying that GSK-3 inhibition alone would interfere with neurogenesis. To overcome this problem, we decided to stimulate neural specification by additionally adding EGF and bFGF [20,43,44].…”

Section: The Crb2-kd Phenotype Can Be Rescued By Gsk3b Inhibition Andmentioning

confidence: 95%

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

Boroviak

Rashbass

2011

Stem Cells

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ESCs undergoing neural differentiation in vitro display an intrinsic heterogeneity with a large subset of the cells forming polarized neural rosettes that maintain the neural progenitor microenvironment. This heterogeneity is not only necessary for normal development but also causes substantial technical challenges for practical applications. Here, we report a novel regulator of early neural progenitors, the apical polarity protein Crb2 (Crumbs homologue 2). Employing monolayer differentiation of mouse ESCs to model neurogenesis in vitro, we find that Crb2 is upregulated with Sox1 and Musashi at the onset of neuroepithelial specification and localizes to the apical side of neural rosettes. Stable Crb2-knockdown (KD) lines die at the onset of neural specification and fail to stabilize several apical polarity proteins. However, these cells are able to proliferate under selfrenewing conditions and can be differentiated into mesodermal and endodermal lineages. Conversely, Crb2 overexpression during neural differentiation results in elevated levels of other apical polarity proteins and increases proliferation. Additionally, sustained overexpression of Crb2 reduces terminal differentiation into TuJ1-positive neurons. Furthermore, we demonstrate that Crb2 overexpression under selfrenewing conditions increases glycogen synthase kinase (GSK)-3b inhibition, correlating with an increase in clonogenicity. To confirm the importance of GSK-3b inhibition downstream of Crb2, we show that Crb2-KD cells can be forced into neural lineages by blocking GSK-3b function and supplementing Epidermal Growth Factor (EGF) and basic Fibroblast Growth Factor (bFGF). Thus, this is the first demonstration that a member of the Crumbs family is essential for survival and differentiation of ESC-derived neural progenitors.

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Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor

Cited by 1,895 publications

References 46 publications

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

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