Wnt signalling and its impact on development and cancer.
ABSTRACT 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.
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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.Journal of Cell Science 09/2014; DOI:10.1242/jcs.149302 · 5.33 Impact Factor
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ABSTRACT: Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.Genes & development 04/2014; 28(8):858-74. DOI:10.1101/gad.233791.113 · 12.64 Impact Factor
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ABSTRACT: To investigate the promoter methylation status at selected loci which encode for key proteins involved in apoptosis, DNA repair, cell cycle control and progression in urothelial cell carcinoma of bladder and compare the findings from tissue samples with that of plasma. Total genomic DNA was isolated from 43 non-muscle invasive (low grade) and 33 muscle invasive (high grade) urothelial bladder cancer samples along with 10 control cases of normal bladder mucosa. Promoter methylation status was investigated for RASSF1A, APC, MGMT, CDKN2A and CDKN2B genes using real-time methylation-specific PCR with SYBR® green. Plasma samples from 16 patients with muscle invasive high grade bladder cancer were also subjected to similar analyses. Promoter hypermethylation was frequently observed in RASSF1A, APC and MGMT gene promoters (p-value < 0.001). The methylation was more prominent in the muscle invasive high grade bladder cancer when compared to non-muscle invasive low grade group (p-value < 0.001) and normal bladder mucosa (p-value < 0.05). The RNA expression of RASSF1A, APC and MGMT was also found to be decreased in the muscle-invasive high grade bladder cancer when compared to the non muscle invasive low grade group (p-value < 0.05). RASSF1A, MGMT and CDKN2A showed comparable results when data from 16 plasma samples was compared to the corresponding tissue samples. Our results suggest that epigenetic silencing of RASSF1A, APC and MGMT genes is strongly associated with invasive high grade urothelial bladder cancer. Thus, status of promoter methylation has the potential to serve as valuable tool for assessing aggressiveness of urothelial cell carcinoma of bladder.SpringerPlus 01/2014; 3(1):178. DOI:10.1186/2193-1801-3-178