A new putative target for antisense gene therapy of glioma: Glycogen synthase
Maryvonne ArdourelMarion BlinJean-Luc MoretThierry DufourHuynh-Thien DucTobias HévorJerzy TrojanJean-François Cloix
9
Citation
0
Reference
10
Related Paper
Citation Trend
Abstract:
The treatment of malignant brain gliomas remains a challenge, despite the availability of the classical triad of surgery, radiotherapy, and chemotherapy. There is thus the need for investigations into other forms of treatment strategies, such as gene therapy. Using antisense technology we have targeted glycogen metabolism, since malignant astrocytes present a high content of glycogen. In vitro rat C6‑glioma cells, transfected with antisense glycogen synthase (C6‑AS cells) exhibited a decreased expression of glycogen synthase and reduced activity of glycogen synthesis, along with attenuated invasiveness. In vivo tumors induced by C6‑AS cells in nude mice exhibited a significant reduction in tumor growth compared with controls. This reduction could be mediated by the induction of MCH‑I expression. The inhibition of glycogen synthesis by antisense glycogen synthase validates a putative target and a new approach for further study to advance the much‑needed efficacy of intervention strategies for malignant gliomas.Keywords:
GSK3B
To investigate the role of the key intracellular signaling molecule glycogen synthase kinase-3 beta in the mechanism of liver ischemia reperfusion (IR).C57BL/6 mice were subjected to 90 min warm liver cephalad lobe ischemia, followed by various length of reperfusion. Experiment groups included sham control group, liver IRI model group and glycogen synthase kinase-3 beta inhibitor-treated group (SB216763 in DMSO, 25 g/kg, i.p, 2 hour prior to the onset of liver ischemia). The expression of glycogen synthase kinase-3 beta protein was analysed by Western blotting. The serum ALT levels were determined to reflect the function of liver. The affected liver lobes were harvested for histology analysis. The inflammatory gene expression was detected by Quantitative PCR.By western blot analysis, we found that ischemia itself activated glycogen synthase kinase-3 beta by a significant decrease of its phosphorylation. Glycogen synthase kinase-3 beta inhibitor SB216763-pretreatment ameliorated the liver damages significantly as compared to the controls (sALT: 2046+/-513 U/L vs 5809+/-1689 U/L, P = 0.0153), and suppressed the gene expressions of IL-12, TNFa, IL-1b and IL-6.This study demonstrated that the ischemia process modulated liver innate immune activation via a GSK-3-dependent mechanism which favored the development of a pro-inflammation response and lead to liver tissue damages. GSK-3b may be a new therapeutic target to ameliorate liver IRI in transplant patients.
GSK3B
Cite
Citations (0)
Clinical Significance
Cite
Citations (22)
Multiple reports suggest that glycogen synthase kinase-3(GSK3)plays an important role in the pathogenesis of Alzheimer's disease(AD).The level and enzymatic activity of GSK3 is elevated in AD.Cell culture studies and animal model studies with both invertebrates and mammals find that over-activity of GSK3 causes hyper-phosphorylation of the tau protein,increased production of β-amyloid,learning and memory impairments,and associated neurodegeneration.GSK-3β inhibitors prevent tau hyper-phosphorylation in AD transgenic animals so they are of potential use in the prevention and treatment of AD.
Pathogenesis
GSK3B
Cite
Citations (0)
GSK3B
Cite
Citations (0)
Human GSK3B wild-type allele is located in the vicinity of 3q13.3 and is approximately 273 kb in length. This allele, which encodes glycogen synthase kinase-3 beta protein, is involved in the negative regulation of glycogen synthesis.
GSK3B
Glycogen debranching enzyme
Cite
Citations (0)
Glycogen synthase kinase 3 (GSK‐3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK‐3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK‐3 activity in PC12 cells using either selective small molecule ATP‐competitive GSK‐3 inhibitors (SB‐216763 and SB‐415286), or adenovirus overexpressing requently earranged in dvanced ‐cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK‐3 activity towards Axin and β‐catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK‐3 activity towards Tau and β‐catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB‐216763 and SB‐415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK‐3 activity towards GS in addition to Tau and β‐catenin.
GSK3B
Dephosphorylation
Cite
Citations (87)
Glycogen synthase kinase 3 (GSK3), a constitutively acting multi‐functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, τ protein and β catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin‐mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti‐diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti‐diabetic but do not lead to up‐regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti‐diabetic therapeutic target. British Journal of Pharmacology (2009) doi:10.1111/j.1476‐5381.2008.00085.x
GSK3B
Cite
Citations (453)
GSK3B
Cite
Citations (215)
Glycogen synthase kinase-3β(GSK-3β) was initially identified as an enzyme involved in glycogen metabolism.GSK-3β phosphorylates a variety of substrates of different biological activities to regulate cellular functions,such as proliferation,differentiation and apoptosis.In the research model of the Parkinson's disease,the increase of GSK-3β activity was recently found to induce neuron apoptosis.On the other hand,when the GSK-3β activity was inhibited,both the tau protein phosphorylation and α-synuclein expression were reduced,then led to neural protection.Therefore,GSK-3β may become a new target for the treatment of Parkinson's disease.
GSK3B
Cite
Citations (0)
Glycogen synthase kinase‐5 (casein kinase‐II) phosphorylates glycogen synthase on a serine termed site 5. This residue is just C‐terminal to the 3 serines phosphorylated by glycogen synthase kinase‐3, which are critical for the hormonal regulation of glycogen synthase in vivo. Although phosphorylation of site 5 does not affect the catalytic activity, it is demonstrated that this modification is a prerequisite for phosphorylation by glycogen synthase kinase‐3. Since site 5 is almost fully phosphorylated in vivo under all conditions, the role of glycogen synthase kinase‐5 would appear to be a novel one in forming the recognition site for another protein kinase
Glycogen branching enzyme
GSK3B
Phosphorylase kinase
Glycogen debranching enzyme
Cite
Citations (177)