Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.
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ABSTRACT:
SUBMITTER: Liu C
PROVIDER: S-EPMC8500522 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The endocannabinoid system is involved in the regulation of many physiological effects in the central and peripheral nervous system. Recent findings have demonstrated the presence of a functional endocannabinoid system within neuronal progenitors located in the hippocampus and ventricular/subventricular zone that participates in the regulation of cell proliferation. It is presently unknown whether the endocannabinoid system exerts a widespread effect on neuronal precursors from different neurogenic regions, and very little is known about the signaling by which it regulates neuronal precursor proliferation. Herein, we demonstrate the presence of cannabinoid CB(1) receptors in granule cell precursors (GCPs) during early cerebellar development. Activation of CB(1) receptors by HU-210 promoted GCP proliferation in vitro, an effect that was prevented by a selective CB(1) antagonist. Accordingly, in vivo experiments showed that GCP proliferation was increased by chronic HU-210 treatment and that in CB(1)-deficient mice cell proliferation was significantly lower than in wild-type littermates, indicating that the endocannabinoid system is physiologically involved in regulation of GCP proliferation. The pro-proliferative effect of cannabinoids in GCPs was mediated through the CB(1)/AKT/glycogen synthase kinase-3beta/beta-catenin pathway. Involvement of this pathway was also observed in cultures of neuronal precursors from the subventricular zone, suggesting that this pathway may be a general mechanism by which endocannabinoids regulate proliferation of neuronal precursors. These observations suggest that endocannabinoids constitute a new family of lipid signaling cues that may exert a widespread effect on neuronal precursor proliferation during brain development.
| S-EPMC2843172 | biostudies-literature
Project description:The human pathogen Helicobacter pylori influences cell adhesion, proliferation, and apoptosis and is involved in gastric adenocarcinoma formation. In our study we analyzed the impact of H. pylori infection on the regulation of beta-catenin, which plays a central role in both cell adhesion and tumorigenesis. Infection of Madin-Darby canine kidney cells with H. pylori led to suppression of Ser/Thr phosphorylation and ubiquitin-dependent degradation of beta-catenin and to up-regulation of lymphoid enhancer-binding factor/T cell factor (LEF/TCF)-dependent transcription. The impaired Ser/Thr phosphorylation of beta-catenin was accompanied by an increase of glycogen synthase kinase 3beta phosphorylation. Inhibition of Akt kinase, an up-stream regulator of glycogen synthase kinase 3, by a specific inhibitor Akti-1/2 or depletion of Akt with siRNA restored Ser/Thr phosphorylation of beta-catenin. We conclude that glycogen synthase kinase 3beta activity exerts an important role in beta-catenin regulation and LEF/TCF transactivation in H. pylori-infected Madin-Darby canine kidney cells.
| S-EPMC2662023 | biostudies-literature
Project description:Lymphatic vessels play an important role in health and in disease. In this study, we evaluated the effects of GSK3-β inhibition on lung lymphatic endothelial cells in vitro. Pharmacological inhibition and silencing of GSK3-β resulted in increased lymphangiogenesis of lung lymphatic endothelial cells. To investigate mechanisms of GSK3-β-mediated lymphangiogenesis, we interrogated the mammalian/mechanistic target of rapamycin pathway and found that inhibition of GSK3-β resulted in PTEN activation and subsequent decreased activation of AKT, leading to decreased p-P70S6kinase levels, indicating inhibition of the mTOR pathway. In addition, consistent with a negative role of GSK3-β in β-catenin stability through protein phosphorylation, we found that GSK3-β inhibition resulted in an increase in β-catenin levels. Simultaneous silencing of β-catenin and inhibition of GSK3-β demonstrated that β-catenin is required for GSK3-β-induced lymphangiogenesis.
| S-EPMC6456176 | biostudies-literature
Project description:Development of innovative more effective therapy is required for refractory osteosarcoma patients. We previously established that glycogen synthase kinase-3β (GSK- 3β) is a therapeutic target in various cancer types. In the present study, we explored the therapeutic efficacy of GSK-3β inhibition against osteosarcoma and the underlying molecular mechanisms in an orthotopic mouse model. Expression and phosphorylation of GSK-3β in osteosarcoma and normal osteoblast cell lines was examined, together with efficacy of GSK-3β inhibition on cell survival, proliferation and apoptosis and on the growth of orthotopically-transplanted human osteosarcoma in nude mice. We also investigated changes in expression, phosphorylation and co-transcriptional activity of β-catenin in osteosarcoma cells following GSK-3β inhibition. Expression of the active form of GSK- 3β (tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells. Inhibition of GSK-3β activity by pharmacological inhibitors or of its expression by RNA interference suppressed proliferation of osteosarcoma cells and induced apoptosis. Treatment with GSK-3β-specific inhibitors attenuated the growth of orthotopic osteosaroma in mice. Inhibition of GSK-3β reduced phosphorylation at GSK- 3β-phospho-acceptor sites in β-catenin and increased β-catenin expression, nuclear localization and co-transcriptional activity. These results suggest the efficacy of GSK-3β inhibitors is associated with activation of β-catenin, a putative tumor suppressor in bone and soft tissue sarcoma and an important component of osteogenesis. Our study thereby demonstrates a critical role for GSK-3β in sustaining survival and proliferation of osteosarcoma cells, and identifies this kinase as a potential therapeutic target against osteosarcoma.
| S-EPMC5363568 | biostudies-literature
Project description:Background/purpose Glycogen synthase kinase-3β (GSK3β) inhibitor enhances bone formation, while dental pulp stem cells (DPSC) are potentially used to repair bone defects. The present study aimed to investigate the effect of AR-A014418 (AR, a specific glycogen synthase kinase-3β inhibitor) on the migration and osteogenic differentiation of rat-derived dental pulp stem cells (rDPSCs), and further explore the underlying mechanism. Materials and methods rDPSCs were isolated from rats, and then cultured with different concentrations of AR with or without LY294002 (a PI3K inhibitor). Then, cell viability, migration, osteogenic differentiation, and the involvement of PI3K pathway were detected by CCK-8 assay, Transwell assay, Alizarin Red S Staining, Alkaline phosphatase (ALP) assay, Western blot, and RT-PCR, respectively. Results Our present study demonstrated that AR of various concentrations (1 μM, 2.5 μM, and 5 μM) not only promoted the rDPSC proliferation and migration, but also increased calcium deposition, the activity of alkaline phosphatase (ALP), and levels of osteogenic markers (RUNX2, OPN, OCN, and OSX) in rDPSCs. It was also found that the administration of AR resulted in an increase in the expression level of p-GSK3β (Ser), β-catenin, p-PI3K, and p-Akt, and a reduction in p-GSK3β (Tyr216). Furthermore, PI3K inhibitor LY294002 abrogated the enhanced cell migration and osteogenic differentiation of rDPSCs induced by AR. Conclusion Our results provide evidence that AR significantly promotes migration and osteogenic differentiation of rDPSCs by activating β-catenin/PI3K/Akt signaling pathway.
| S-EPMC9201544 | biostudies-literature
Project description:Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with cancers in immunocompromised populations. EBV establishes a latent infection and immortalizes and transforms B lymphocytes. Several latent proteins have profound effects on cellular growth, including activation of NF-kappaB, phosphatidylinositol 3'-OH kinase (PI3K) signaling, and notch signaling. Activation of PI3K can affect the activity of beta-catenin, the target of the wnt signaling pathway. Deregulation of beta-catenin is associated with a number of malignancies. To determine if beta-catenin is regulated by EBV infection, EBV-infected cells were examined for beta-catenin levels and localization. beta-Catenin was increased in EBV-positive tumor cell lines compared to EBV-negative lines, in EBV-infected Burkitt's lymphoma cell lines, and in EBV-transformed lymphoblastoid cell lines (LCL). In contrast to wnt signaling, EBV consistently induced the accumulation of beta-catenin in the cytoplasm but not the nucleus. The beta-catenin regulating kinase, glycogen synthase kinase 3beta (GSK3beta), was shown to be phosphorylated and inactivated in EBV-infected lymphocytes. Inactivated GSK3beta was localized to the nucleus of EBV-infected LCL. Neither the cytoplasmic accumulation of beta-catenin nor the nuclear inactivation of GSK3beta was affected by the inhibition of PI3K signaling. These data indicate that latent infection with EBV has unique effects on beta-catenin signaling that are distinct from activation of wnt and independent of its effects on PI3K.
| S-EPMC523297 | biostudies-literature
Project description:Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3β (glycogen synthase kinase-3β) activity and upregulating β-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.
| S-EPMC8751936 | biostudies-literature
Project description:Progesterone secretion by the steroidogenic cells of the corpus luteum (CL) is essential for reproduction. Progesterone synthesis is under the control of LH, but the exact mechanism of this regulation is unknown. It is established that LH stimulates the LH receptor/choriogonadotropin receptor, a G-protein coupled receptor, to increase cAMP and activate cAMP-dependent protein kinase A (PKA). In the present study, we tested the hypothesis that cAMP/PKA-dependent regulation of the Wnt pathway components glycogen synthase kinase (GSK)-3beta and beta-catenin contributes to LH-dependent steroidogenesis in luteal cells. We observed that LH via a cAMP/PKA-dependent mechanism stimulated the phosphorylation of GSK3beta at N-terminal Ser9 causing its inactivation and resulted in the accumulation of beta-catenin. Overexpression of N-terminal truncated beta-catenin (Delta90 beta-catenin), which lacks the phosphorylation sites responsible for its destruction, significantly augmented LH-stimulated progesterone secretion. In contrast, overexpression of a constitutively active mutant of GSK3beta (GSK-S9A) reduced beta-catenin levels and inhibited LH-stimulated steroidogenesis. Chromatin immunoprecipitation assays demonstrated the association of beta-catenin with the proximal promoter of the StAR gene, a gene that expresses the steroidogenic acute regulatory protein, which is a cholesterol transport protein that controls a rate-limiting step in steroidogenesis. Collectively these data suggest that cAMP/PKA regulation of GSK3beta/beta-catenin signaling may contribute to the acute increase in progesterone production in response to LH.
| S-EPMC3213761 | biostudies-literature
Project description:Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) to regulate diverse biological functions from cell growth to apoptosis. Drugs that mimic their action are the most commonly prescribed therapeutic agents in the world and are currently used for the treatment of many diseases including asthma, autoimmune disorders, and some cancers. However, the mechanisms by which one hormone, via one receptor, modulates such diverse biological functions remain unclear. We hypothesized that epigenetic alteration to the GR may contribute to its signaling diversity, and here we demonstrate that Glycogen Synthase Kinase-3-beta phosphorylates GR on Serine 404 in a glucocorticoid-dependent manner. U-2 OS cells expressing a mutant GR that is incapable of Ser404 phosphorylation have enhanced global transcriptional responses, stronger NF-kappaB transrepression, and enhanced cell death in response to dexamethasone. Conversely, presence of Ser404 phosphorylation on the GR inhibits glucocorticoid-dependent NF-kappaB transrepression and cell death of these osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3-beta pathway with the GR resulting in altered glucocorticoid regulated signaling. Our results also provide a mechanism by which the phosphorylation status of Ser404 in GR can dictate how cells will ultimately respond to GCs. Keywords: Glucocorticoid Receptor; GSK-3-beta; NF-kappaB Transrepression; Phosphorylation
2008-11-24 | GSE11205 | GEO
Project description:BackgroundGlioblastoma multiforme stem cells display a highly chemoresistant phenotype, whose molecular basis is poorly known. We aim to clarify this issue and to investigate the effects of temozolomide on chemoresistant stem cells.MethodsA panel of human glioblastoma cultures, grown as stem cells (neurospheres) and adherent cells, was used.ResultsNeurospheres had a multidrug resistant phenotype compared with adherent cells. Such chemoresistance was overcome by apparently noncytotoxic doses of temozolomide, which chemosensitized glioblastoma cells to doxorubicin, vinblastine, and etoposide. This effect was selective for P-glycoprotein (Pgp) substrates and for stem cells, leading to an investigation of whether there was a correlation between the expression of Pgp and the activity of typical stemness pathways. We found that Wnt3a and ABCB1, which encodes for Pgp, were both highly expressed in glioblastoma stem cells and reduced by temozolomide. Temozolomide-treated cells had increased methylation of the cytosine-phosphate-guanine islands in the Wnt3a gene promoter, decreased expression of Wnt3a, disrupted glycogen synthase-3 kinase/β-catenin axis, reduced transcriptional activation of ABCB1, and a lower amount and activity of Pgp. Wnt3a overexpression was sufficient to transform adherent cells into neurospheres and to simultaneously increase proliferation and ABCB1 expression. On the contrary, glioblastoma stem cells silenced for Wnt3a lost the ability to form neurospheres and reduced at the same time the proliferation rate and ABCB1 levels.ConclusionsOur work suggests that Wnt3a is an autocrine mediator of stemness, proliferation, and chemoresistance in human glioblastoma and that temozolomide may chemosensitize the stem cell population by downregulating Wnt3a signaling.
| S-EPMC3813413 | biostudies-literature