PRDM1 is directly targeted by miR-30a-5p and modulates the Wnt/β-catenin pathway in a Dkk1-dependent manner during glioma growth
Xuan WangKun WangLei HanAnling ZhangZhendong ShiKailiang ZhangHongwei ZhangShaohua YangPeiyu PuChanghong ShenChunjiang YuChunsheng Kang
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Bone remodeling, which plays an important role in maintaining bone homeostasis and its structural adaptation to mechanical environment, is regulated by various kinds of molecular signals. Wnt signaling is one of the most important factors in bone remodeling, particularly in bone formation. To reveal the Wnt signaling and its inhibition mechanisms, we measured the interaction between Wnt signal receptor, LRP5, and its signaling molecules, Wnt3a, Dkk1, and Sclerostin, by using Atomic Force Microscope (AFM). In this study, we calculated the dissociation constants of Wnt3a/LRP5, sclerostin/LRP5, and Dkk1/LRP5, and it was proved that the dissociation constant of Dkk1/LRP5 is about 10-times smaller than that of sclerostin/LRP5, that is, the bond life time of Dkk1/LRP5 was about 10-times longer than that of sclerostin/LRP5. As the results, we quantitatively verified a previous suggestion that Dkk1 may function as a main regulator of Wnt signaling, and that sclerostin, which is more selective in its activity and restricted in its expression, may function as a more refined regulator of Wnt signaling.
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Signaling of the secreted wingless-type MMTV integration site (WNT) has been implicated as a driving factor in osteoarthritis (OA). The induction of chondrocyte hypertrophy is a role attributed to WNT in OA, which may explain why chondrocytes in articular cartilage express high levels of WNT antagonists to modulate the activity of WNT signaling. Dickkopf 1 homolog (DKK1) and frizzled-related protein (FRZB) are naturally occurring antagonists of the WNT signaling pathway. Previously, we identified DKK1 and FRZB as key factors in controlling the articular chondrocyte phenotype by preventing endochondral ossification. The aim of this thesis is to study the role of WNT signaling and its antagonists DKK1 and FRZB in human articular cartilage. In this thesis, we have provided answers for the following questions: i) how does expression of joint-related factors change in cartilage and synovial fluid during OA progression, with a focus on the changes in expression of WNT and WNT antagonists; ii) what is the fundamental role of WNT/β-catenin signaling and its antagonists (DKK1 and FRZB) in human chondrocytes and mesenchymal stem cells; iii) how are WNT antagonists regulated by the inflammatory factor IL1β; and iv) how can we use our knowledge to improve the understanding OA pathology and its treatment.
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Mao et al. isolated a binding partner for the Wnt signaling inhibitor Dickkopf1 (Dkk1) by expression cloning. This binding partner was a member of the Kremen family of transmembrane proteins, and subsequent analysis showed that Dkk1 and Dkk2 both bound to Kremen1 and Kremen2. Contransfection of Dkk1 and Kremen1 or Kremen2 inhibited Wnt signaling measured as change in reporter gene expression. Wnt signaling is initiated by interactions with two receptors: Frizzled and LRPS or LRPG. Dkk1 promoted the interaction of Kremen2 with LPR6, and in transfected cells, Dkk stimulated the endocytosis of LRP6 and Dkk1. Thus, Dkk proteins may inhibit Wnt signaling by stimulating the removal of one of the Wnt receptor partners from the cell surface. B. Mao, W. Wu, G. Davidson, J. Marhold, M. Li, B. M. Mechler, H. Dellus, D. Hoppe, P. Stannek, C. Walter, A. Glinka, C. Niehrs, Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417 , 664-667 (2002). [Online Journal]
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Osteoblast differentiation requires the interaction of various cell signaling pathways to modulate cell responses. Notch and Wnt signaling are among the crucial pathways that control numerous biological processes, including osteo/odontogenic differentiation. The aim of the present study was to examine the involvement of Wnt signaling in the Jagged1-induced osteo/odontogenic differentiation in human dental pulp stem cells (hDPSCs). The Wnt-related gene expression was analyzed from publicly available data of Jagged1-treated human dental pulp cells. The mRNA expression of Wnt ligands (WNT2B, WNT5A, WNT5B, and WNT16) and Wnt inhibitors (DKK1, DKK2, and SOST) were confirmed using real-time polymerase chain reaction. Among the Wnt ligands, WNT2B and WNT5A mRNA levels were upregulated after Jagged1 treatment. In contrast, the Wnt inhibitors DKK1, DKK2, and SOST mRNA levels were downregulated. Recombinant WNT5A, but not WNT2B, significantly promoted in vitro mineral deposition by hDPSCs. Wnt signaling inhibition using IWP-2, but not DKK1, inhibited Jagged1-induced alkaline phosphatase (ALP) activity, mineralization, and osteo/odontogenic marker gene expression in hDPSCs. In conclusion, Jagged1 promoted hDPSC osteo/odontogenic differentiation by modulating the non-canonical Wnt pathway.
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Limbal epithelial stem/progenitor cells (LSCs) are adult stem cells located at the limbus, tightly regulated by their close microenvironment. It has been shown that Wnt signaling pathway is crucial for LSCs regulation. Previous differential gene profiling studies confirmed the preferential expression of specific Wnt ligands (WNT2, WNT6, WNT11, WNT16) and Wnt inhibitors (DKK1, SFRP5, WIF1, FRZB) in the limbal region compared to the cornea. Among all frizzled receptors, frizzled7 (Fzd7) was found to be preferentially expressed in the basal limbal epithelium. However, the exact localization of Wnt signaling molecules-producing cells in the limbus remains unknown. The current study aims to evaluate the in situ spatial expression of these 4 Wnt ligands, 4 Wnt inhibitors, and Fzd7. Wnt ligands, DKK1, and Fzd7 expression were scattered within the limbal epithelium, at a higher abundance in the basal layer than the superficial layer. SFRP5 expression was diffuse among the limbal epithelium, whereas WIF1 and FRZB expression was clustered at the basal limbal epithelial layer corresponding to the areas of high levels of Fzd7 expression. Quantitation of the fluorescence intensity showed that all 4 Wnt ligands, 3 Wnt inhibitors (WIF1, DKK1, FRZB), and Fzd7 were highly expressed at the basal layer of the limbus, then in a decreasing gradient toward the superficial layer (P < 0.05). The expression levels of all 4 Wnt ligands, FRZB, and Fzd7 in the basal epithelial layer were higher in the limbus than the central cornea (P < 0.05). All 4 Wnt ligands, 4 Wnt inhibitors, and Fzd7 were also highly expressed in the limbal stroma immediately below the epithelium but not in the corneal stroma (P < 0.05). In addition, Fzd7 had a preferential expression in the superior limbus compared to other limbal quadrants (P < 0.05). Taken together, the unique expression patterns of the Wnt molecules in the limbus suggests the involvement of both paracrine and autocrine effects in LSCs regulation, and a fine balance between Wnt activators and inhibitors to govern LSC fate.
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The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo.
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Abstract Introduction: Wnt signaling in cells with mutationally-induced constitutive pathway activation promotes clonogenic growth and epithelial-mesenchymal transition (EMT). The role of autocrine Wnt signals in colon cancer cells lacking a Wnt pathway activating mutation is less clear. Hypothesis: Extracellular Wnt inhibitors will reduce clonogenic growth and EMT in colon cancer cell lines lacking mutational Wnt pathway activation by inhibiting basal levels of autocrine Wnt signaling. Methods: Two cells lines were utilized: HCT116B is a colon cancer cell line in which an abnormal beta-catenin allele has been removed by homologous recombination; RKO is a colon cancer cell line with no known Wnt pathway activation. The Wnt inhibitors DKK1, which blocks canonical Wnt signals by interaction with LRP5 and sFRP1 which blocks both canonical and non-canonical Wnt signals were utilized and transfected into each cell line. Canonical Wnt throughput was measured with a luciferase based reporter construct, clonogenic growth by colony formation in soft agar and EMT by morphology. Results: Untransfected HCT116B, but not RKO expressed DKK1. Neither cell line expressed sFRP1. Both cell lines expressed significant quantities of DKK1 or sFRP1 after transfection. Canonical Wnt signaling was suppressed in RKO by both DKK1 and sFRP1 but only by DKK1 in HCT116B. DKK1 inhibited clonogenic growth in RKO but not in HCT116B, while sFRP1 inhibited it in both cell lines. EMT was clearly suppressed by these inhibitors in RKO; such an effect was less visible in HCT116B. Discussion: Colon cancer cells lacking mutational activation of the Wnt pathway are susceptible to the actions of extracellular Wnt inhibitors, presumably via inhibition of autocrine Wnt signals and canonical Wnt signaling. However, cells with basal expression of a canonical Wnt inhibitor such as DKK1 (HCT116B) rely preferentially on non-canonical pathways for clonogenic growth and EMT which can be blocked by global Wnt ligand antagonists such as sFRP1. The importance of autocrine Wnt signaling and contributions by non-canonical pathways to clonogenic growth and EMT has important implications for the development of Wnt-targeted therapeutic agents for colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-362. doi:10.1158/1538-7445.AM2011-LB-362
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Wnt-beta-catenin signaling controls critical events in metazoan development, and its dysregulation leads to cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane co-receptors Frizzled (Fz) and low-density lipoprotein (LDL) receptor-related protein (LRP) 5 or LRP6 inhibits the degradation of the transcriptional coactivator beta-catenin, which translocates to the nucleus to regulate gene expression. The secreted protein Dickkopf1 (Dkk1) inhibits Wnt signaling by binding to LRP5 and LRP6 and blocking their interaction with Wnt and Fz. Kremen 1 and 2 (Krm1 and 2, collectively termed Krms) are single-pass transmembrane Dkk1 receptors that synergize with Dkk1 to inhibit Wnt signaling by promoting the endocytosis of LRP5 and LRP6. A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane. It is proposed that the absence or presence of Dkk1 determines whether Krms will activate or inhibit Wnt-beta-catenin signaling, respectively. Here, we speculate that the proposed context-dependent positive and negative roles for Krms could promote biphasic Wnt signaling in response to a shallow gradient of Dkk1, resulting in the generation of precise and robust borders between cells during development. Identification of a context-dependent role for Krms in Wnt-beta-catenin signaling offers insight into the mechanism of Wnt signaling and has important developmental implications.
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