Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

McCubrey, James A.; Steelman, Linda S.; Bertrand, F. E.; Davis, Nicole M.; Abrams, Stephen L.; Montalto, Giuseppe; D’Assoro, Antonino B.; Libra, Massimo; Nicoletti, Ferdinando; Maestro, Roberta; Bäsecke, Jörg; Cocco, Lucio; Cervello, Melchiorre; Martelli, Alberto M.

doi:10.1038/leu.2013.184

Cited by 206 publications

(181 citation statements)

References 154 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…Interestingly, when pretreatment control cells with LiCl in the absence of miR-10a mimic transfection, the β-catenin protein expression, as well as ALP, Runx2, Osx, OC, DLX5 mRNA levels, and cell migration, tube formation has been significantly increased compare with the control group. Moreover, as LiCI is not very specific and also Gsk3-β has many other targets [20]. Therefore, all these results were confirmed by Gsk3-β knock down and also β-catenin overexpression.…”

Section: Resultssupporting

confidence: 70%

MicroRNA-10a Influences Osteoblast Differentiation and Angiogenesis by Regulating β-Catenin Expression

Zhang

Zhao

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Elucidation of the molecular mechanisms governing osteoblast differentiation and angiogenesis are of great importance for improving the treatment of bone-related diseases. In this study, we examined the role of microRNA (miR)-10a in the differentiation of MC3T3-E1 cells and pro angiogenic activity of mouse umbilical vein endothelial cells (MUVECs). Methods: The murine pre-osteoblast cell line MC3T3-E1 and MUVECs were used in the experiment. After transfected with miR-10a mimics or inhibitors, with or without LiCl pretreatment, the miR-10a, ALP, Runx2, Osx, OC and Dlx5 expression were assessed by RT-PCR. MC3T3-E1 cells were cultured with BMP2 to differentiate into bone cells, osteogenic differentiation of MC3T3-E1 cells were detected by ALP and ARS staining. Cell viability were analyzed by MTT and the protein expression of β-catenin, LEF1, cyclinD1, MMP2, and VEGF were detected by Western blotting; VEGF and VE-cadherin release were assessed by ELISA, and the migration of MUVECs, as well as tube formation were also detected. Results: MiR-10a expression was obviously down-regulated during osteogenic differentiation. Overexpression of miR-10a inhibited osteogenic differentiation of MC3T3-E1 cells, effectively decreasing MUVECs proliferation, migration, VEGF expression, VE-cadherin concentrations, and tube formation in vitro, whereas miR-10a silence enhanced those processes. Further mechanism assays demonstrated that overexpression of miR-10a reduced the β-catenin at both protein and transcription level, while pretreatment with Wnt signaling activator Licl partially attenuated the suppression effects of miR-10a overexpression on osteoblast differentiation and angiogenesis. Conclusion: Our findings imply that miR-10a plays a suppressive role in osteoblast differentiation of MC3T3-E1 cells and pro angiogenic activity of MUVECs by regulating the β-catenin expression, representing a novel and potential therapeutic target for the treatment of bone regeneration-related diseases.

show abstract

Section: Resultssupporting

confidence: 70%

MicroRNA-10a Influences Osteoblast Differentiation and Angiogenesis by Regulating β-Catenin Expression

Zhang

Zhao

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…β-Catenin is a multifunctional protein that has structural importance in the adhesive junction complex and the ability to bind to AR to stimulate AR-mediated gene transcription (17). β-catenin expression was measured in LNCaP/shCD147 and LNCaP/Scramble cells by western blotting.…”

Section: Resultsmentioning

confidence: 99%

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

et al. 2016

View full text Add to dashboard Cite

Abstract. The androgen signaling pathway serves an important role in the development of prostate cancer. β-Catenin is an androgen receptor (AR) cofactor and augments AR signaling. Glycogen synthase kinase-3β (GSK-3β), a target of phosphorylated serine/threonine protein kinase B (p-Akt), regulates β-catenin stability. In addition, β-catenin, a coregulator of AR, physically interacts with AR and enhances AR-mediated target gene transcription. The multifunctional glycoprotein cluster of differentiation (CD) 147 is highly expressed on the cell surface of the majority of cancer cells, and it promotes tumor invasion, metastasis and growth. In the present study, the molecular effects of CD147 on the Akt/GSK-3β/β-catenin/AR signaling network were investigated in LNCaP cells. Using short hairpin-mediated RNA knockdown of CD147 in LNCaP cells, it was demonstrated that downregulation of CD147 resulted in inhibitory phosphorylation of GSK-3β, and then promoted degeneration of β-catenin and reduced nuclear accumulation of β-catenin. In addition, immunoprecipitation studies demonstrated that CD147 downregulation decreased the formation of a complex between β-catenin and AR. It was shown that CD147 knockdown suppressed the expression of the AR target gene prostate-specific antigen and the growth of AR-positive LNCaP cells. Furthermore, inhibition of PI3K/Akt with LY294002 augmented CD147-mediated function. The present study indicates that the PI3K/Akt pathway may facilitate CD147-mediated activation of the AR pathway.

show abstract

“…Furthermore, the AKT signaling pathway seems to be implicated in fibrosis because its inhibition can reduce collagen production by human fibroblasts (26,27). Moreover, this pathway can affect b-catenin by inhibiting GSK3b and stabilizing b-catenin (28,29).…”

mentioning

confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

show abstract

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Cited by 206 publications

References 154 publications

MicroRNA-10a Influences Osteoblast Differentiation and Angiogenesis by Regulating β-Catenin Expression

MicroRNA-10a Influences Osteoblast Differentiation and Angiogenesis by Regulating β-Catenin Expression

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Contact Info

Product

Resources

About