scholarly journals The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.

1996 ◽  
Vol 10 (12) ◽  
pp. 1443-1454 ◽  
Author(s):  
C Yost ◽  
M Torres ◽  
J R Miller ◽  
E Huang ◽  
D Kimelman ◽  
...  
Keyword(s):  
Subcellular Distribution ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Beta Catenin ◽  
Xenopus Embryos

scholarly journals Oxidative stress-induced downregulation of glycogen synthase kinase 3 beta in fetal membranes promotes cellular senescence†

2019 ◽  
Vol 101 (5) ◽  
pp. 1018-1030 ◽  
Author(s):  
Narmada Lavu ◽  
Lauren Richardson ◽  
Enkhtuya Radnaa ◽  
Talar Kechichian ◽  
Rheanna Urrabaz-Garza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Western Blot ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Fetal Membrane ◽  
Related Factor ◽  
Beta Catenin

Abstract Objective Oxidative stress (OS)-induced stress signaler p38 mitogen-activated protein kinase (p38MAPK) activation and fetal membrane senescence are associated with parturition. This study determined changes in glycogen synthase kinase 3 beta (GSK3β) and its regulation by p38MAPK in effecting senescence to further delineate the molecular mechanism involved in senescence. Methods Primary human amnion epithelial cells and amnion mesenchymal cells were treated with cigarette smoke extract (CSE, OS inducer). Expression of total and phosphorylated GSK3β and p38MAPK, and that of GSK3β’s downstream targets: beta-catenin (β-Cat) and nuclear factor erythroid 2-related factor 2 (Nrf2) (western blot analysis), cell cycle regulation and senescence (flow cytometry) were determined. The specificity of GSK3β and p38MAPK’s mechanistic role was tested by co-treating cells with their respective inhibitors, CHIR99021 and SB203580. Exosomal secretion of β-Cat from OS-induced cells was confirmed by immunofluorescence confocal microscopy and western blot. Results OS induced by CSE resulted in phosphorylation of GSK3β (inactivation) and p38MAPK (activation) that was associated with cell cycle arrest and senescence. Inhibitors to GSK3β and p38MAPK verified their roles. Glycogen synthase kinase 3 beta inactivation was associated with nuclear translocation of antioxidant Nrf2 and exosomal secretion of β-Cat. Conclusions OS-induced P-p38MAPK activation is associated with functional downregulation of GSK3β and arrest of cell cycle progression and senescence of amnion cells. Lack of nuclear translocation of β-Cat and its excretion via exosomes further supports the postulation that GSK3β down-regulation by p38MAPK may stop cell proliferation preceding cell senescence. A better understanding of molecular mechanisms of senescence will help develop therapeutic strategies to prevent preterm birth.

Selective Inhibition of Glycogen Synthase Kinase-3 by Facilitators of Insulin Response Promotes Proliferation and Survival in Multiple Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4789-4789
Author(s):  
Helena Jernberg-Wiklund ◽  
Thomas Stromberg ◽  
Anna Hammarberg ◽  
Patrik Georgii-Hemming ◽  
Anders Osterborg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Glycogen Synthase ◽  
Insulin Response ◽  
Cyclin B1 ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Serum Starvation ◽  
Beta Catenin ◽  
Ample Evidence

Abstract There is ample evidence for a central role of IGF-1R in multiple myeloma (MM) cell survival and resistance to apoptosis. Recently, we have demonstrated the use of inhibitors of the IGF-1R tyrosine kinase (RTK) activity as a promising therapeutic strategy in MM in vitro and in vivo (Stromberg et al Blood 2006,107:669–78, Menu et al Int J Cancer 2007,121:1857–61). In the present investigation, we have examined the role of glycogen synthase kinase-3 (GSK3), a target of the IGF-1R/PI 3-K/AKT pathway, in proliferation and apoptosis of MM. Unlike most kinases GSK3 is constitutively active, but may be inhibited by e.g. insulin, EGF and FGF. GSK3 is also a converging point of the Wnt and the IGF-1R/PI 3-K/AKT survival pathway. Reduction of GSK3 activity resulted from its phosphorylation at the regulatory residues Ser21 (α isoform) and Ser9 (β isoform) catalysed by AKT. GSK3 inhibitors LiCl, AR-A014418, the maleimides SB216763 and SB41528, and the highly selective aminopyrimidine derivatives CT98014 and CT99021 (Novartis, Emeryville, CA), were investigated for their effects on MM cells when growth and survival were challenged by cytotoxic stress and/or interference with different signaling proteins. Apoptosis induced by serum starvation was reduced by CT99021, an effect comparable to the survival-promoting effect of IGF-1. The selective GSK3 inhibitor also restored survival in MM cells induced by glucocorticoids and combinations increasing the susceptibility to apoptosis using PI 3-K inhibitors LY294002, the IGF-1R antagonist αIR3, the mTOR inhibitor rapamycin and the MEK inhibitor PD98059. In addition to the anti-apoptotic effect, CT99021 was also demonstrated to counteract G0/G1 accumulation induced by serum starvation, LY294002, αIR3 and rapamycin. However, accumulation of cells in the G2/M phase induced by doxorubicin and melphalan, were not counteracted by GSK3 inhibitors. Substrates of GSK3 most prominently include beta-catenin and the IκB-analog Bcl-3, both targeted for degradation upon GSK3 activation. Selective GSK inhibition restituted protein levels of beta-catenin, Bcl-3, p21 cip1/WAF1, p27kip1 and cyclin B1, D2 and E corroborating with the effects on survival and proliferation. These data demonstrate that targeting of the GSK3 using highly selective inhibitors is associated with potent anti-apoptotic effects and propagation through the cell cycle in MM.

scholarly journals Erratum: Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos

Nature ◽  
1995 ◽  
Vol 375 (6528) ◽  
pp. 253-253 ◽  
Author(s):  
Xi He ◽  
Jean-Pierre Saint-Jeannet ◽  
James R. Woodgett ◽  
Harold E. Varmus ◽  
Igor B. Dawid
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Dorsoventral Patterning ◽  
Xenopus Embryos

Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos

Nature ◽  
1995 ◽  
Vol 374 (6523) ◽  
pp. 617-622 ◽  
Author(s):  
Xi He ◽  
Jean-Pierre Saint-Jeannet ◽  
James R. Woodgett ◽  
Harold E. Varmus ◽  
Igor B. Dawid
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Dorsoventral Patterning ◽  
Xenopus Embryos
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