Unfolded Protein Response Is Required for the Definitive Endodermal Specification of Mouse Embryonic Stem Cells via Smad2 and β-Catenin Signaling

Xu, Huiming; Tsang, Kam Sze; Wang, Yonghui; Chan, Juliana C.N.; Xu, Gang; Gao, Wei‐Qiang

doi:10.1074/jbc.m114.572560

Cited by 29 publications

(39 citation statements)

References 42 publications

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“…This unexpected role for UPR signaling in corticogenesis is further substantiated by the time-dependent downregulation of UPR we observed in WT progenitors ( Figure 7K). Together with other recent findings (Heijmans et al, 2013;Rosekrans et al, 2015;Xu et al, 2014), our results uncover an active role of the UPR in governing the balance between proliferation and differentiation in different tissues. Progenitor Enrichment by Magnetic-Activated Cell Sorting Typically, 10-20 cortices (E12.5 to E16.5 embryos) were pooled, digested by papain (20 min at 37 C and stopped by addition of 1 volume of ovomucoid), and single cells were filtrated on a 50 mM cell stainer (Greiner Bio One).…”

Section: Elongator Is a Hub That Coordinates Generation And Maturatiosupporting

confidence: 87%

“…Expression of Tbr2 in cortical extracts from E14.5 WT or Elp3cKO measured by western blot (O) and normalized on b actin (P; 100.0% ± 1.3% for WT and 44.9% ± 5.8% for Elp3cKO, ***p < 0.001, t test; n = 3 brains per condition) or Sox2 (Q; 100.0% ± 10.6% for WT and 27.8% ± 1.6% for Elp3cKO, ***p < 0.001, t test; n = 3 brains per condition). IPs (Tbr2, red), undergoing S phase (BrdU, green) (R) or M phase (pHH3; green) (T) in E14.5 Elp3cKO expressed as (legend continued on next page) Upregulation of UPR Mediates Neurogenesis Defects in the Elp3cKO Developing Cortex UPR contributes to physiological processes such as cell differentiation during development (Heijmans et al, 2013;Xu et al, 2014) and their induction is associated with several disorders occurring during adulthood (Katayama et al, 2004;Wang and Kaufman, 2014). To determine if upregulation of UPR triggers the cortical neurogenesis defects seen upon Elp3 depletion, we blocked Atf4 upregulation by electroporation of esiRNAs ( Figure S7A).…”

Section: Loss Of Elp3 Expression Triggers the Unfolded Protein Responmentioning

confidence: 99%

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A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis

et al. 2015

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The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.

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Section: Elongator Is a Hub That Coordinates Generation And Maturatiosupporting

confidence: 87%

Section: Loss Of Elp3 Expression Triggers the Unfolded Protein Responmentioning

confidence: 99%

A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis

et al. 2015

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“…60 Activation of UPR results in the differentiation of definitive endoderm cells from mouse ESCs and inhibition of UPR prevents the specific differentiation. 61 UPR components Xbp1 and Hrd1 restrict the proliferative activity of ISCs in the intestinal epithelium. 62 In addition, ER stress is also implicated in the embryonic development of CNS, 44 and all three branches of UPR were induced during neuronal differentiation of rat bone marrow stromal cells and mouse embryonic stem cells.…”

Section: Discussionmentioning

confidence: 99%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.

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“…Additionally, the inhibition of ART, DHA, and ARTS in Wnt/β-catenin activation was also confirmed in tumor tissues collected from xenograft model in vivo (Figure 6E ). Given the significant inhibition of Wnt/β-catenin pathway in ART, DHA, and ARTS treatments, we further determined the molecular target of ART, DHA, and ARTS using Wnt5a siRNA as well as IWP-2, specific inhibitor of Wnt/β-catenin pathway [ 53 ]. Compared with IWP-2, no significant difference in G1 arrest was observed in IWP-2 combined with ART, DHA, and ARTS, respectively, indicating that Wnt/β-catenin signaling pathway was probably the most vital pathway influenced by ART, DHA, and ARTS (Figure 5B ).…”

Section: Discussionmentioning

confidence: 99%

Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling

et al. 2016

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Non-small-cell lung cancer (NSCLC) is the most prevalent malignancy worldwide given its high incidence, considerable mortality, and poor prognosis. The anti-malaria compounds artemisinin (ART), dihydroartemisinin (DHA), and artesunate (ARTS) reportedly have anti-cancer potential, although the underlying mechanisms remain unclear. In this work, we used flow cytometry to show that ART, DHA, and ARTS could inhibit the proliferation of A549 and H1299 cells by arresting cell cycle in G1 phase. Meanwhile, tumor malignancy including migration, invasion, cancer stem cells, and epithelial–mesenchymal transition were also significantly suppressed by these compounds. Furthermore, ART, DHA, and ARTS remarkably decreased tumor growth in vivo. By using IWP-2, the inhibitor of Wnt/β-catenin pathway, and Wnt5a siRNA, we found that ART, DHA, and ARTS could render tumor inhibition partially dependent on Wnt/β-catenin inactivation. These compounds could strikingly decrease the protein level of Wnt5-a/b and simultaneously increase those of NKD2 and Axin2, ultimately resulting in β-catenin downregulation. In summary, our findings revealed that ART, DHA, and ARTS could suppress lung-tumor progression by inhibiting Wnt/β-catenin pathway, thereby suggesting a novel target for ART, DHA, and ARTS in cancer treatment.

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Unfolded Protein Response Is Required for the Definitive Endodermal Specification of Mouse Embryonic Stem Cells via Smad2 and β-Catenin Signaling

Cited by 29 publications

References 42 publications

A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis

A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling

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