Glucocorticoid receptor β regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/TCF transcriptional activity

Yin, Ying; Zhang, Xiufen; Li, Zaiwang; Deng, Ling-Xiao; Jiao, Guoqing; Zhang, Bin; Xie, Ping; Mu, Hui-Jun; Qiao, Wei; Zou, Jian

doi:10.1016/j.nbd.2013.07.013

Cited by 42 publications

(48 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lentiviral GRβ shRNA and scramble vector were purchased from Genechem. The target sequence of shRNA for GRβ was described in a previous study [9]. Cell lines > 90% purity were used in subsequent experiments.…”

Section: Cell Culturementioning

confidence: 99%

“…Several reports have shown that aberrant activation of Wnt/β-catenin/TCF signaling is an important contributing factor in glioma development (Ref) [11][12][13]. Our previous finding that GRβ is predominately distributed in the nucleus and contributes to glioma pathogenesis raises the consideration that the cross-talk between GRβ and β-catenin/TCF signaling involves in the progression of glioma [9].…”

Section: Introductionmentioning

confidence: 95%

“…While, GRα is predominately located in cytoplasm under hormone-free condition [10], suggesting GRα exerts its trans-repression on β-catenin-TCF signaling is hormone dependent. Our recent study demonstrated that GRβ enhances β-catenin-TCF signaling through negative regulation of GRα function in the presence of hormone [9]. Mechanically, the interplay between GRβ and β-catenin was demonstrated to be a necessary component of astrocyte reactivity through sustained Wnt/β-catenin/TCF signaling in its dominant-negative effect on GRα mediated trans-repression by a GSK-3β-independent manner.…”

Section: Introductionmentioning

confidence: 95%

“…GRα acts as a trans-repressor on β-catenin-TCF signaling [7][8][9]. While, GRα is predominately located in cytoplasm under hormone-free condition [10], suggesting GRα exerts its trans-repression on β-catenin-TCF signaling is hormone dependent.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

Wang

Shi

et al. 2014

Mol Neurobiol

Self Cite

View full text Add to dashboard Cite

We previously reported that glucocorticoid receptor β (GRβ) regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/ T-cell factor/Lymphoid enhancer factor (TCF/LEF) transcriptional activity. The aim of this study was to characterize the mechanism behind cross-talk between GRβ and β-catenin/TCF in the progression of glioma. Here, we reported that GRβ knock-down reduced U118 and Shg44 glioma cell proliferation in vitro and in vivo. Mechanistically, we found that GRβ knock-down decreased TCF/LEF transcriptional activity without affecting β-catenin/TCF complex. Both GRα and GRβ directly interact with TCF-4, while only GRβ is required for sustaining TCF/LEF activity under hormone-free condition. GRβ bound to the N-terminus domain of TCF-4 its influence on Wnt signaling required both ligand binding and DNA-binding domains (LBD and DBD, respectively). GRβ and TCF-4 interaction is enough to maintain the TCF/LEF activity at a high level in the absence of β-catenin stabilization.Taken together, these results suggest a novel cross-talk between GRβ and TCF-4 which regulates Wnt signaling and the proliferation in gliomas.

show abstract

Section: Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

Wang

Shi

et al. 2014

Mol Neurobiol

Self Cite

View full text Add to dashboard Cite

show abstract

“…27,28 Furthermore, this isoform was found to participate in the molecular pathways of glioma formation as well as in the migration of bladder cancer cells. [29][30][31] In addition to in vitro and animal experiments, studies in humans have shown that hGRβ expression levels are associated with glucocorticoid resistance in severa l inflammatory diseases (ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, asthma), hematologic malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia) as well as in many mood disorders (major depression, schizophrenia). 18,32 In contradistinction to hGRβ, the hGRα isoform is ubiquitously expressed in every tissue except the SCN Figure 1.…”

Section: Glucocorticoid Receptor: From the Nr3c1 Gene To Protein Isofmentioning

confidence: 99%

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

Nicolaides

Charmandari

2017

View full text Add to dashboard Cite

Glucocorticoids play a fundamental role in many physiologic functions and contribute substantially to the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated by a ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), which may influence the transcription rate of numerous target genes, interact with other transcription factors, trigger the activation of several kinase pathways or modulate mitochondrial DNA expression. Any genetic defects in the NR3C1 gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologic conditions characterized by partial impaired tissue sensitivity to glucocorticoids. However, there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1 gene. In these cases, several other factors might influence the glucocorticoid signal transduction. In this review, we discuss the numerous glucocorticoid functions and the multiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoid signaling cascade and we summarize the clinical manifestations and pathogenesis of Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculate that the next generation sequencing technologies will undoubtedly enable us to gain a deeper understanding of the GR "interactome".

show abstract

The positive regulatory loop of TCF4N/p65 promotes glioblastoma tumourigenesis and chemosensitivity

Zhang

et al. 2022

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Background NF‐κB signaling is widely linked to the pathogenesis and treatment resistance in cancers. Increasing attention has been paid to its anti‐oncogenic roles, due to its key functions in cellular senescence and the senescence‐associated secretory phenotype (SASP). Therefore, thoroughly understanding the function and regulation of NF‐κB in cancers is necessary prior to the application of NF‐κB inhibitors. Methods We established glioblastoma (GBM) cell lines expressing ectopic TCF4N, an isoform of the β‐catenin interacting transcription factor TCF7L2, and evaluated its functions in GBM tumorigenesis and chemotherapy in vitro and in vivo. In p65 knock‐out or phosphorylation mimic (S536D) cell lines, the dual role and correlation of TCF4N and NF‐κB signaling in promoting tumorigenesis and chemosensitivity was investigated by in vitro and in vivo functional experiments. RNA‐seq and computational analysis, immunoprecipitation and ubiquitination assay, minigene splicing assay and luciferase reporter assay were performed to identify the underlying mechanism of positive feedback regulation loop between TCF4N and the p65 subunit of NF‐κB. A eukaryotic cell‐penetrating peptide targeting TCF4N, 4N, was used to confirm the therapeutic significance. Results Our results indicated that p65 subunit phosphorylation at Ser 536 (S536) and nuclear accumulation was a promising prognostic marker for GBM, and endowed the dual functions of NF‐κB in promoting tumorigenesis and chemosensitivity. p65 S536 phosphorylation and nuclear stability in GBM was regulated by TCF4N. TCF4N bound p65, induced p65 phosphorylation and nuclear translocation, inhibited its ubiquitination/degradation, and subsequently promoted NF‐κB activity. p65 S536 phosphorylation was essential for TCF4N‐led senescence‐independent SASP, GBM tumorigenesis, tumor stem‐like cell differentiation and chemosensitivity. Activation of p65 was closely connected to alterative splicing of TCF4N, a likely positive feedback regulation loop between TCF4N and p65 in GBM. 4N increased chemosensitivity, highlighting a novel anti‐cancer strategy. Conclusion Our study defined key roles of TCF4N as a novel regulator of NF‐κB through mutual regulation with p65 and provided a new avenue for GBM inhibition.

show abstract

Glucocorticoid receptor β regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/TCF transcriptional activity

Cited by 42 publications

References 54 publications

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

The positive regulatory loop of TCF4N/p65 promotes glioblastoma tumourigenesis and chemosensitivity

Contact Info

Product

Resources

About