Klaus A, Birchmeier W.. Wnt signaling and its impact on development and cancer. Nat Rev Cancer 8: 387-398
Max Delbrück Centre for Molecular Medicine, Robert-Roessle-Strasse 10, 13,125 Berlin, Germany. Nature Reviews Cancer
(Impact Factor: 37.4).
06/2008; 8(5):387-98. DOI: 10.1038/nrc2389
The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.
Available from: Xuemin He
- "As a result, stabilized b-catenin accumulates in the cytosol and translocates to the nucleus. It then associates with T cell factor (TCF) to activate transcription of Wnt target genes including cyclin D1 (Ccnd1), Myc protooncogene (Myc), vascular endothelial growth factor (VEGF), and Axin2 (Klaus and Birchmeier, 2008). Wnt/b-catenin signaling plays central roles in the regulation of multiple physiological processes (Clevers, 2006). "
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ABSTRACT: The Wnt pathway plays important roles in multiple physiological and pathophysiological processes. Here we report a novel mechanism regulating the Wnt pathway through heterodimerization of lipoprotein receptor-related protein (LRP6), a Wnt co-receptor and very low-density lipoprotein receptor (VLDLR), which is in the same family as LRP6 and was originally known as a receptor for lipoproteins. Knockdown of Vldlr expression elevated LRP6 levels and activated Wnt/β-catenin signaling, whereas over-expression of Vldlr suppressed Wnt signaling. Moreover, we demonstrated that the VLDLR ectodomain is essential and sufficient for inhibition of Wnt signaling. The VLDLR ectodomain accelerated internalization and degradation of LRP6 through heterodimerization with the LRP6 extracellular domain. Monoclonal antibodies specific for the VLDLR ectodomain blocked VLDLR:LRP6 heterodimerization, resulting in enhanced Wnt/β-catenin signaling in vitro and in vivo. Taken together, these findings suggest that heterodimerization of receptors in the membrane accelerates LRP6 turnover, and represent a new mechanism for regulation of Wnt/β-catenin signaling.
- "In addition to being an epithelial cell marker, β-Catenin also transduces canonical Wnt signals and is implicated in cell proliferation . Cytoplasmic β-Catenin is stabilized upon activation of Wnt signaling, leading to its translocation to the nucleus, where it interacts with T-cell factors (TCFs) to stimulate the transcription of target genes. "
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While the endothelium-organ interaction is critical for regulating cellular behaviors during development and disease, the role of blood flow in these processes is only partially understood. The dorsal aorta performs paracrine functions for the timely migration and differentiation of the sympatho-adrenal system. However, it is unclear how the adrenal cortex and medulla achieve and maintain specific integration and whether hemodynamic forces play a role.
Methodology and Principal Findings
In this study, the possible modulation of steroidogenic and chromaffin cell integration by blood flow was investigated in the teleostean counterpart of the adrenal gland, the interrenal gland, in the zebrafish (Danio rerio). Steroidogenic tissue migration and angiogenesis were suppressed by genetic or pharmacologic inhibition of blood flow, and enhanced by acceleration of blood flow upon norepinephrine treatment. Repressed steroidogenic tissue migration and angiogenesis due to flow deficiency were recoverable following restoration of flow. The regulation of interrenal morphogenesis by blood flow was found to be mediated through the vascular microenvironment and the Fibronectin-phosphorylated Focal Adhesion Kinase (Fn-pFak) signaling. Moreover, the knockdown of krüppel-like factor 2a (klf2a) or matrix metalloproteinase 2 (mmp2), two genes regulated by the hemodynamic force, phenocopied the defects in migration, angiogenesis, the vascular microenvironment, and pFak signaling of the steroidogenic tissue observed in flow-deficient embryos, indicating a direct requirement of mechanotransduction in these processes. Interestingly, epithelial-type steroidogenic cells assumed a mesenchymal-like character and downregulated β-Catenin at cell-cell junctions during interaction with chromaffin cells, which was reversed by inhibiting blood flow or Fn-pFak signaling. Blood flow obstruction also affected the migration of chromaffin cells, but not through mechanosensitive or Fn-pFak dependent mechanisms.
Conclusions and Significance
These results demonstrate that hemodynamically regulated Fn-pFak signaling promotes the migration of steroidogenic cells, ensuring their interaction with chromaffin cells along both sides of the midline during interrenal gland development.
Available from: Hua Zhou
- "Previous reports have demonstrated that DKK1 can suppress the Wnt-induced signaling that is frequently activated in tumor biology . Consequently, the reduction and loss of DKK1 expression as a tumor-suppressive activity have been reported in human cancers such as malignant melanoma and colon cancer , . "
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Dickkopf-1 (DKK1) is an antagonist of Wnt/β-catenin signaling implicated in tumorigenesis. However, the biological role of DKK1 and β-catenin involved in chondrosarcoma has not been sufficiently investigated. This study was designed to investigate the expression profiles of DKK1 and β-catenin, and to clarify their clinical values in chondrosarcoma.
The mRNA and protein levels of DKK1 and β-catenin in fresh chondrosarcoma and the corresponding non-tumor tissues were analyzed by Real-time PCR and Western blot, respectively. The protein expression patterns of DKK1 and β-catenin were investigated by immunohistochemistry. The associations among DKK1 level, β-catenin accumulation, clinicopathological factors and the overall survival were separately evaluated.
Both DKK1 and β-catenin levels were remarkably elevated in chondrosarcoma compared with the corresponding non-tumor tissues. High DKK1 level and positive β-catenin accumulation in chondrosarcoma specimens were 58.7% and 53.9%, respectively. Elevated DKK1 level significantly correlated with positive β-catenin accumulation, and they were remarkably associated with histological grade and Musculoskeletal Tumor Society stage. Furthermore, DKK1 level and β-catenin accumulation had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that DKK1 level was an independent prognostic factor for overall survival.
Elevated DKK1 levels associated with β-catenin accumulation play a crucial role in chondrosarcoma. DKK1 can serve as a novel predictor of poor prognosis in patients with chondrosarcoma.
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