Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

Breunig, Joshua J.; Levy, Rachelle; Antonuk, C. Danielle; Molina, Jéssica; Dutra‐Clarke, Marina; Park, Hannah; Akhtar, Aslam Abbasi; Kim, Gi Bum; Town, Terrance; Hu, Xiangyou; Bannykh, Serguei; Danielpour, Moise

doi:10.1016/j.celrep.2016.12.026

Cited by 12 publications

(11 citation statements)

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“…A TagBFP2 blue fluorescent protein with a hemagglutinin (HA) epitope tag (TagBFP-HA)-nuclear localization sequence reporter and pBase were coelectroporated to facilitate counting of tumor cells and for transposition, respectively. Neural precursor cells along the rostro-caudal axis of the left lateral ventricle where plasmids were delivered were susceptible to electroporation and subsequently transformed by KrasG12V (31,33). Mouse brains were analyzed at 4 and 8 wk postelectroporation to monitor tumor growth.…”

Section: Resultsmentioning

confidence: 99%

BCL6 promotes glioma and serves as a therapeutic target

Chen

Dutra‐Clarke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.

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Section: Resultsmentioning

confidence: 99%

BCL6 promotes glioma and serves as a therapeutic target

Chen

Dutra‐Clarke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the mechanism responsible for neurofibromin/MEK-driven multilineage differentiation has not been elucidated. Two transcription factors, Erm and Ascl1, can regulate gliogenesis in response to elevated RAS/ERK signaling (Li et al 2012;Breunig et al 2015). While Nf1 −/− NSCs exhibit increased Erm expression by quantitative RT-PCR (qRT-PCR) and Western blotting, this was not attenuated following MEK inhibition (PD901) (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways

2015

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Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/ AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation. Collectively, these findings establish distinct roles for the RAS effector pathways in regulating brain NSC function.

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“…Pathways such as Rap1 signalling pathway, 33,34 pathway in cancer and insulin signalling pathway 35,36 which were previously implicated in gliomas were significantly enriched in differentially spliced genes in subtype 1 (Figure A). Similarly, AS events in subtype 3 comprised crucial pathways reported in gliomas, including Ras signalling pathway 37,38 and cAMP signalling pathway 39,40 (Figure B). Our analyses revealed that differential AS events participated in many important biological process and pathways involved in glioma pathogenesis.…”

Section: Resultsmentioning

confidence: 82%

Characterization and prognostic significance of alternative splicing events in lower‐grade diffuse gliomas

Zhao

Liu

et al. 2020

J Cellular Molecular Medi

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Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower‐grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower‐grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower‐grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype‐differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower‐grade diffuse gliomas were profiled. Subtype‐differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer‐related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS‐related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower‐grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower‐grade diffuse gliomas.

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Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

Cited by 12 publications

References 0 publications

BCL6 promotes glioma and serves as a therapeutic target

BCL6 promotes glioma and serves as a therapeutic target

Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways

Characterization and prognostic significance of alternative splicing events in lower‐grade diffuse gliomas

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