scholarly journals Relaxin reverses maladaptive remodeling of the aged heart through Wnt-signaling

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Brian Martin ◽  
Beth Gabris ◽  
Amr F. Barakat ◽  
Brian L. Henry ◽  
Marianna Giannini ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Healthy Aging ◽  
Ventricular Myocytes ◽  
Therapeutic Potential ◽  
Electrical Remodeling ◽  
Dependent Manner ◽  
Aged Rats ◽  
Canonical Wnt ◽  
Dickkopf 1 ◽  
Fundamental Mechanism

AbstractHealthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases. Relaxin, an insulin-like hormone, suppresses atrial fibrillation, inflammation and fibrosis in aged rats but the mechanisms-of-action are unknown. Here we show that relaxin treatment of aged rats reverses pathological electrical remodeling (increasing Nav1.5 expression and localization of Connexin43 to intercalated disks) by activating canonical Wnt signaling. In isolated adult ventricular myocytes, relaxin upregulated Nav1.5 (EC50 = 1.3 nM) by a mechanism inhibited by the addition of Dickkopf-1. Furthermore, relaxin increased the levels of connexin43, Wnt1, and cytosolic and nuclear β-catenin. Treatment with Wnt1 or CHIR-99021 (a GSK3β inhibitor) mimicked the relaxin effects. In isolated fibroblasts, relaxin blocked TGFβ-induced collagen elevation in a Wnt dependent manner. These findings demonstrate a close interplay between relaxin and Wnt-signaling resulting in myocardial remodeling and reveals a fundamental mechanism of great therapeutic potential.

scholarly journals Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 196-207 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Yu Chen ◽  
Owen Stephens ◽  
Nathan Brown ◽  
Bangzheng Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Protein Production ◽  
Osteoclast Differentiation ◽  
Bone Lesions ◽  
Dependent Manner ◽  
Rankl Expression ◽  
Receptor Activator ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell–derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios.

scholarly journals DKK1 activates noncanonical NF-κB signaling via IL-6–induced CKAP4 receptor in multiple myeloma

2021 ◽  
Vol 5 (18) ◽  
pp. 3656-3667
Author(s):  
Xin Li ◽  
Jingjing Wang ◽  
Shuai Zhu ◽  
Jinxin Zheng ◽  
Ying Xie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Wnt Signaling ◽  
Proteasome Inhibitors ◽  
Bone Destruction ◽  
Bortezomib Treatment ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

2005 ◽  
Vol 333 (4) ◽  
pp. 1300-1308 ◽  
Author(s):  
Fumiko Yano ◽  
Fumitaka Kugimiya ◽  
Shinsuke Ohba ◽  
Toshiyuki Ikeda ◽  
Hirotaka Chikuda ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Chondrocyte Differentiation ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

scholarly journals Analysis of Endogenous LRP6 Function Reveals a Novel Feedback Mechanism by Which Wnt Negatively Regulates Its Receptor

2007 ◽  
Vol 27 (20) ◽  
pp. 7291-7301 ◽  
Author(s):  
Zahid Khan ◽  
Sapna Vijayakumar ◽  
Teresa Villanueva de la Torre ◽  
Sabrina Rotolo ◽  
Anna Bafico
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Mrna Level ◽  
Cellular Membrane ◽  
Feedback Mechanism ◽  
Bone Diseases ◽  
Dependent Manner ◽  
Direct Role ◽  
Initial Stimulus ◽  
Canonical Wnt

ABSTRACT The canonical Wnt pathway plays a crucial role in embryonic development, and its deregulation is involved in human diseases. The LRP6 single-span transmembrane coreceptor is essential for transmission of canonical Wnt signaling. However, due to the lack of immunological reagents, our understanding of LRP6 structure and function has relied on studies involving its overexpression, and regulation of the endogenous receptor by the Wnt ligand has remained unexplored. Using a highly sensitive and specific antibody to LRP6, we demonstrate that the endogenous receptor is modified by N-glycosylation and is phosphorylated in response to Wnt stimulation in a sustained yet ligand-dependent manner. Moreover, following triggering by Wnt, endogenous LRP6 is internalized and recycled back to the cellular membrane within hours of the initial stimulus. Finally, we have identified a novel feedback mechanism by which Wnt, acting through β-catenin, negatively regulates LRP6 at the mRNA level. Together, these findings contribute significantly to our understanding of LRP6 function and uncover a new level of regulation of Wnt signaling. In light of the direct role that the Wnt pathway plays in human bone diseases and malignancies, our findings may support the development of novel therapeutic approaches that target Wnt signaling through LRP6.

scholarly journals Multiple Wnts act synergistically to induce Chk1/Grapes expression and mediate G2 arrest in Drosophila tracheoblasts

2020 ◽  
Author(s):  
Amrutha Kizhedathu ◽  
Rose Sebastian Kunnappallil ◽  
Archit V Bagul ◽  
Puja Verma ◽  
Arjun Guha
Keyword(s):  
Wnt Signaling ◽  
Kinase Activity ◽  
Developmental Regulation ◽  
Wnt Signalling ◽  
Dependent Manner ◽  
G2 Arrest ◽  
Tracheal System ◽  
G2 Phase ◽  
Canonical Wnt ◽  
Atr Kinase

ABSTRACTLarval tracheae of Drosophila harbor progenitors of the adult tracheal system (tracheoblasts). Thoracic tracheoblasts are arrested in the G2 phase of the cell cycle in an ATR (mei-41)-Checkpoint Kinase1 (grapes, Chk1) dependent manner prior to mitotic re-entry. Here we investigate developmental regulation of Chk1 activation. We report that Wnt signaling is high in tracheoblasts and is necessary for high levels of activated (phosphorylated) Chk1. We find that canonical Wnt signaling facilitates this by transcriptional upregulation of Chk1 expression in cells that have ATR kinase activity. Wnt signalling is dependent on four Wnts (Wg, Wnt5, 6,10) that are expressed at high levels in arrested tracheoblasts and downregulated at mitotic re-entry. Interestingly, none of the Wnts are dispensable and act synergistically to induce Chk1. Finally, we show that downregulation of Wnt signalling and Chk1 expression leads to mitotic re-entry and the concomitant upregulation of Dpp signalling, driving tracheoblast proliferation.

scholarly journals Deregulation of the histone H3K9 di-methylation landscape suppresses canonical Wnt signaling in embryonal rhabdomyosarcoma

2020 ◽  
Author(s):  
Ananya Pal ◽  
Jia Yu Leung ◽  
Gareth Chin Khye Ang ◽  
Vinay Kumar Rao ◽  
Luca Pignata ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Myogenic Differentiation ◽  
Wnt Signaling Pathway ◽  
Embryonal Rhabdomyosarcoma ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Therapeutic Modalities ◽  
Canonical Wnt

AbstractThe Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the H3K9 lysine methyltransferase G9a suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of G9a expression or activity reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in vivo. Mechanistically, G9a impacted Sp1 and p300 enrichment at the DKK1 promoter in a methylation-dependent manner. The reduced tumor growth upon G9a deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability. Together, our study demonstrates that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1-β-catenin node holds promise for differentiation therapy.

scholarly journals Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

2020 ◽  
Author(s):  
Yueli Liu ◽  
Jiawen Wang ◽  
Corrigan Horton ◽  
Sol Katzman ◽  
Tao Cai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Target Genes ◽  
Critical Role ◽  
Gene Set Enrichment Analysis ◽  
Dependent Manner ◽  
Basal Cells ◽  
Canonical Wnt Signaling ◽  
Cell Functions ◽  
Canonical Wnt

AbstractBoth the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling down-regulated the expressions of a Wnt reporter as well as many Wnt target genes. Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and β–catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.

scholarly journals Chlorogenic Acids Inhibit Adipogenesis: Implications of Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Mengting Liu ◽  
Jian Qin ◽  
Jing Cong ◽  
Yubin Yang
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Fatty Acid Synthase ◽  
Adipocyte Differentiation ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Ppar Γ ◽  
Gsk 3Β ◽  
Canonical Wnt

In our previous in vitro study, we found that chlorogenic acid (CGA) inhibited adipocyte differentiation and triglyceride (TG) accumulation, but the underlying mechanism is still unclear. Accumulative genetic evidence supports that canonical Wnt signaling is a key modulator on adipogenesis. Methods. In this study, 3T3-L1 cells were induced adipogenic differentiation and then treated with CGA. We investigate the effect of CGA in inhibiting adipogenesis and evaluate its role in modulating Wnt10b (wingless integration1 10b), β-catenin, glycogen synthase kinase-3β (GSK-3β), and peroxisome proliferator-activated receptor γ (PPAR-γ) involved in the Wnt (wingless integration1)/β-catenin signaling pathway. Results. The result showed that after CGA treatment, lipid accumulation and TG level decreased significantly in 3T3-L1 cells, indicating that CGA could inhibit adipogenesis. In addition, CGA repressed the induction of adipocyte differentiation biomarkers as PPAR-γ, adipocyte protein 2 (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL), and the secretion of GSK-3β in a dose-dependent manner upregulated the expression of β-catenin and Wnt10b both in gene and protein levels. Moreover, CGA induced phosphorylation of GSK-3β and promoted the accumulation of free cytosolic β-catenin in 3T3-L1 adipocytes. Conclusion. Overall, these findings gave us the implications that CGA inhibits adipogenesis via the canonical Wnt signaling pathway.

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