Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the β-Catenin/T-Cell Factor Signaling Pathway

2006 ◽  
Vol 20 (12) ◽  
pp. 3336-3350 ◽  
Author(s):  
Yuen Lam Pon ◽  
Alice S. T. Wong
Keyword(s):  
T Cell ◽  
Small Interfering Rna ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Factor ◽  
Ovarian Surface Epithelial ◽  
Cox 2 ◽  
Induced Apoptosis ◽  
Interfering Rna

Abstract Gonadotropins play a prominent role in ovarian function and pathology. We have shown that treatment with gonadotropins (FSH and LH/human chorionic gonadotropin) reduces the amount of N-cadherin with a concomitant induction of apoptosis in human ovarian surface epithelial (OSE) cells, but precise molecular mechanisms remain to be elucidated. Here, we demonstrated activation of β-catenin/T-cell factor (TCF) signaling by gonadotropins. We further showed that ectopic expression of N-cadherin was sufficient to recruit β-catenin to the plasma membrane, thereby blocking β-catenin/TCF-mediated transactivation in gonadotropin-treated cells. Transfection with β-catenin small interfering RNA or expression of dominant negative TCF inhibited apoptosis, whereas expression of dominant stable β-catenin (S37A) caused significant apoptosis, thus supporting a proapoptotic role for β-catenin/TCF in human OSE. In addition, we showed that gonadotropins enhanced β-catenin/TCF transcriptional activity through inactivation of glycogen synthase kinase-3β in a phosphatidylinositol 3-kinase/Akt-dependent manner, indicating cross talk between the phosphatidylinositol 3-kinase/Akt and β-catenin signaling pathways through glycogen synthase kinase-3β. Furthermore, gonadotropins increased cyclooxygenase-2 (COX-2) expression via the β-catenin/TCF pathway. COX-2 also played a role in gonadotropin-induced apoptosis, as treatment with the COX-2-specific inhibitor NS-398 or COX-2 small interfering RNA blocked gonadotropin-dependent apoptotic activity. These findings suggest that the participation of β-catenin in adhesion and signaling may represent a novel mechanism through which gonadotropins may regulate the cellular fate of human OSE.

scholarly journals ERK1/2 Antagonizes Glycogen Synthase Kinase-3β-induced Apoptosis in Cortical Neurons

2002 ◽  
Vol 277 (51) ◽  
pp. 49577-49584 ◽  
Author(s):  
Michal Hetman ◽  
Shih-Ling Hsuan ◽  
Agata Habas ◽  
Matthew J. Higgins ◽  
Zhengui Xia
Keyword(s):  
Cortical Neuron ◽  
Cortical Neurons ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Activation ◽  
Induced Apoptosis ◽  
Neuron Apoptosis ◽  
Constitutively Active

Inhibition of glycogen synthase kinase-3β (GSK3β) is one of the mechanisms by which phosphatidylinositol 3-kinase (PI3K) activation protects neurons from apoptosis. Here, we report that inhibition of ERK1/2 increased the basal activity of GSK3β in cortical neurons and that both ERK1/2 and PI3K were required for brain-derived neurotrophic factor (BDNF) suppression of GSK3β activity. Moreover, cortical neuron apoptosis induced by expression of recombinant GSK3β was inhibited by coexpression of constitutively active MKK1 or PI3K. Activation of both endogenous ERK1/2 and PI3K signaling pathways was required for BDNF to block apoptosis induced by expression of recombinant GSK3β. Furthermore, cortical neuron apoptosis induced by LY294002-mediated activation of endogenous GSK3β was blocked by expression of constitutively active MKK1 or by BDNF via stimulation of the endogenous ERK1/2 pathway. Although both PI3K and ERK1/2 inhibited GSK3β activity, neither had an effect on GSK3β phosphorylation at Tyr-216. Interestingly, PI3K (but not ERK1/2) induced the inhibitory phosphorylation of GSK3β at Ser-9. Significantly, coexpression of constitutively active MKK1 (but not PI3K) still suppressed neuronal apoptosis induced by expression of the GSK3β(S9A) mutant. These data suggest that activation of the ERK1/2 signaling pathway protects neurons from GSK3β-induced apoptosis and that inhibition of GSK3β may be a common target by which ERK1/2 and PI3K protect neurons from apoptosis. Furthermore, ERK1/2 inhibits GSK3β activity via a novel mechanism that is independent of Ser-9 phosphorylation and likely does not involve Tyr-216 phosphorylation.

scholarly journals Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

2008 ◽  
Vol 198 (3) ◽  
pp. 511-521 ◽  
Author(s):  
Hyunju Chung ◽  
Sanghee Seo ◽  
Minho Moon ◽  
Seungjoon Park
Keyword(s):  
Glycogen Synthase ◽  
Glucose Deprivation ◽  
Glycogen Synthase Kinase ◽  
Protective Effects ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
Unacylated Ghrelin ◽  
Gsk 3Β ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist d-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3β (GSK-3β). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of β-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and stabilization of β-catenin contribute to the anti-apoptotic effects of ghrelin.

scholarly journals Interaction between Smad7 and β-Catenin: Importance for Transforming Growth Factor β-Induced Apoptosis

2005 ◽  
Vol 25 (4) ◽  
pp. 1475-1488 ◽  
Author(s):  
Sofia Edlund ◽  
So Young Lee ◽  
Susanne Grimsby ◽  
Shouthing Zhang ◽  
Pontus Aspenström ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Small Interfering Rna ◽  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Transforming Growth Factor Β ◽  
Specific Factor ◽  
Dependent Manner ◽  
Induced Apoptosis ◽  
Interfering Rna

ABSTRACT Members of the transforming growth factor β (TGF-β) and Wnt/wingless superfamilies regulate cell fate during development and tissue maintenance. Here we report that Smad7 interacts with β-catenin and lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), transcriptional regulators in Wnt signaling, in a TGF-β-dependent manner. Smad7 was found to be required for TGF-β1-induced accumulation of β-catenin and LEF1 in human prostate cancer (PC-3U) cells as well as in human keratinocytes (HaCaT cells). Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF-β-induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3β phosphorylated on Ser9 was prevented, as well as the TGF-β-induced association between β-catenin and LEF1. Notably, the observed physical association of Smad7 and β-catenin was found to be important for TGF-β-induced apoptosis, since suppression of β-catenin expression by small interfering RNA decreased the apoptotic response to TGF-β.

Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines

2016 ◽  
Vol 94 (3) ◽  
pp. 247-255 ◽  
Author(s):  
Ruiting Li ◽  
Yinghui Li ◽  
Xin Hu ◽  
Haiwei Lian ◽  
Lei Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glioblastoma Multiforme ◽  
Cell Lines ◽  
Normal Brain ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Factor ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration ◽  
Transcription Factor 3

Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase–Akt and MAPK–Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways.

scholarly journals Modulation of CD8+ memory stem T cell activity and glycogen synthase kinase 3β inhibition enhances anti-tumoral immunity in gastric cancer

2018 ◽  
Vol 7 (4) ◽  
pp. e1412900 ◽  
Author(s):  
Jin-yu Zhang ◽  
Yong-liang Zhao ◽  
Yi-pin Lv ◽  
Ping Cheng ◽  
Weisan Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Glycogen Synthase ◽  
Cell Activity ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β
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