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Wnt Target Genes (wnt + target_gene)
Selected AbstractsCoordinated expression of cyclin D1 and LEF-1/TCF transcription factor is restricted to a subset of hepatocellular carcinomaLIVER INTERNATIONAL, Issue 4 2005Annette Schmitt-Graeff Abstract: Background: While the Wnt pathway has been widely implicated in hepatocarcinogenesis, the role of cyclin D1 as a direct downstream target gene of ,-catenin-lymphoid enhancer factor-1 (LEF-1)/T-cell factor (TCF) signaling is controversely discussed. Methods: By immunohistochemical analyses we studied the subcellular localization of LEF-1/TCF and cyclin D1 in 162 hepatocellular carcinoma (HCC). Single- and double-label imaging by brightfield and confocal laser scanning microscopy was quantitated and correlated with ,-catenin, the Ki67+ proliferation fraction (PF), tumor size, grade, the Okuda stage and patient survival. Results: The frequency of nuclear cyclin D1 expression was 28% and closely correlated with LEF-1/TCF (P<0.0001) and the Ki67+ PF (P=0.03). Nuclear LEF-1/TCF expression was observed in 52% of all cases, but was also present in 42% of cyclin D1, cases. Nuclear ,-catenin was identified in 37% of all HCCs and correlated with LEF-1/TCF (P=0.04). The expression of cyclin D1, LEF-1/TCF or ,-catenin did not correlate with other clinico-pathological data. Conclusions: A large proportion of HCCs does not appear to be linked to a deregulation of cyclin D1. However, the coordinated expression of cyclin D1 and LEF-1/TCF in some cases suggests the role of cyclin D1 as a Wnt target gene in a subset of HCCs. [source] Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signalingJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Christopher M. Amantea Abstract Osteoporosis and its complications cause morbidity and mortality in the aging population, and result from increased bone resorption by osteoclasts in parallel with decreased bone formation by osteoblasts. A widely accepted strategy for improving bone health is targeting osteoprogenitor cells in order to stimulate their osteogenic differentiation and bone forming properties through the use of osteoinductive/anabolic factors. We previously reported that specific naturally occurring oxysterols have potent osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells. In the present report, we further demonstrate the molecular mechanism(s) by which oxysterols induce osteogenesis. In addition to activating the hedgehog signaling pathway, oxysterol-induced osteogenic differentiation is mediated through a Wnt signaling-related, Dkk-1-inhibitable mechanism. Bone marrow stromal cells (MSC) treated with oxysterols demonstrated increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes. These oxysterol effects, which occurred in the absence of ,-catenin accumulation or TCF/Lef activation, were inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk-1. Furthermore, the inhibitors of PI3-Kinase signaling, LY 294002 and wortmanin, inhibited oxysterol-induced osteogenic differentiation and induction of Wnt signaling target genes. Finally, activators of canonical Wnt signaling, Wnt3a and Wnt1, inhibited spontaneous, oxysterol-, and Shh-induced osteogenic differentiation of bone marrow stromal cells, suggesting the involvement of a non-canonical Wnt pathway in pro-osteogenic differentiation events. Osteogenic oxysterols are, therefore, important small molecule modulators of critical signaling pathways in pluripotent mesenchymal cells that regulate numerous developmental and post-developmental processes. J. Cell. Biochem. 105: 424,436, 2008. © 2008 Wiley-Liss, Inc. [source] Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/,-catenin signaling pathway,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009Macarena S. Arrázola Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of ,-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide. J. Cell. Physiol. 221: 658,667, 2009. © 2009 Wiley-Liss, Inc. [source] Frizzled-1 is involved in the neuroprotective effect of Wnt3a against A, oligomersJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2008Marcelo A. Chacón The activation of the canonical Wnt signaling pathway protects hippocampal neurons against the toxicity of Alzheimer's amyloid-,-peptide (A,), however, the role played by the Wnt receptors Frizzleds, has not been studied. We report here that Frizzled-1 mediates the activation of the canonical Wnt/,-catenin pathway by Wnt3a in PC12 cells. In addition, the protective effect of Wnt3a against the toxicity of A, oligomers was modulated by Frizzled-1 expression levels in both PC12 cells and hippocampal neurons. Over-expression of Frizzled-1 significantly increased cell survival induced by Wnt3a and diminished caspase-3 activation, while knocking-down Frizzled-1 expression by antisense oligonucleotides decreased the Wnt3a protection. Over-expression of wild-type ,-catenin, but not a transcriptionally inactive mutated version, prevented the toxicity of A, suggesting that the transcription of Wnt target genes may be involved in these events. This was confirmed by co-transfecting both Frizzled-1 and the inactive form of ,-catenin, which does not elicited protection levels similar to those showed with endogenous ,-catenin. Our results indicate that Wnt3a protects from A,-oligomers toxicity by activating the canonical Wnt signaling pathway through the Frizzled-1 receptor, suggesting a therapeutic potential for this signaling pathway in the treatment of Alzheimer's disease. J. Cell. Physiol. 217: 215,227, 2008. © 2008 Wiley-Liss, Inc. [source] Pulsating fluid flow modulates gene expression of proteins involved in Wnt signaling pathways in osteocytesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 10 2009Ana Santos Abstract Strain-derived flow of interstitial fluid activates signal transduction pathways in osteocytes that regulate bone mechanical adaptation. Wnts are involved in this process, but whether mechanical loading modulates Wnt signaling in osteocytes is unclear. We assessed whether mechanical stimulation by pulsating fluid flow (PFF) leads to functional Wnt production, and whether nitric oxide (NO) is important for activation of the canonical Wnt signaling pathway in MLO-Y4 osteocytes. MC3T3-E1 osteoblasts were studied as a positive control for the MLO-Y4 osteocyte response to mechanical loading. MLO-Y4 osteocytes and MC3T3-E1 osteoblasts were submitted to 1-h PFF (0.7,±,0.3 Pa, 5 Hz), and postincubated (PI) without PFF for 0.5,3 h. Gene expression of proteins related to the Wnt canonical and noncanonical pathways were studied using real-time polymerase chain reaction (PCR). In MLO-Y4 osteocytes, PFF upregulated gene expression of Wnt3a, c-jun, connexin 43, and CD44 at 1,3-h PI. In MC3T3-E1 osteoblasts, PFF downregulated gene expression of Wnt5a and c-jun at 0.5,3-h PI. In MLO-Y4 osteocytes, gene expression of PFF-induced Wnt target genes was suppressed by the Wnt antagonist sFRP4, suggesting that loading activates the Wnt canonical pathway through functional Wnt production. The NO inhibitor L-NAME suppressed the effect of PFF on gene expression of Wnt target genes, suggesting that NO might play a role in PFF-induced Wnt production. The response to PFF differed in MC3T3-E1 osteoblasts. Because Wnt signaling is important for bone mass regulation, osteocytes might orchestrate loading-induced bone remodeling through, among others, Wnts. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1280,1287, 2009 [source] | ||||||||||