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Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase

Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF(V600E) has also been implicated in neurodegeneration. The present study aims to characterize BRAF(V600E) during cell death a...

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Autores principales: Ye, Qing, Srivastava, Pranay, Al-Kuwari, Nasser, Chen, Xiqun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer - Medknow 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075110/
https://www.ncbi.nlm.nih.gov/pubmed/36571370
http://dx.doi.org/10.4103/1673-5374.361516
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author Ye, Qing
Srivastava, Pranay
Al-Kuwari, Nasser
Chen, Xiqun
author_facet Ye, Qing
Srivastava, Pranay
Al-Kuwari, Nasser
Chen, Xiqun
author_sort Ye, Qing
collection PubMed
description Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF(V600E) has also been implicated in neurodegeneration. The present study aims to characterize BRAF(V600E) during cell death and proliferation of three major cell types of the central nervous system: neurons, astrocytes, and microglia. Multiple primary cultures (primary cortical mixed culture) and cell lines of glial cells (BV2) and neurons (SH-SY5Y) were employed. BRAF(V600E) and BRAF(WT) expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors (extracellular signal-regulated kinase 1/2 and JNK1/2) were achieved by siRNA. In astrocytes and microglia, BRAF(V600E) induces cell proliferation, and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase, but not c-Jun N-terminal kinase. Conditioned medium from BRAF(V600E)-expressing microglia induced neuronal death. In neuronal cells, BRAF(V600E) directly induces neuronal death, through c-Jun N-terminal kinase but not extracellular signal-regulated kinase. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.
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spelling pubmed-100751102023-04-06 Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase Ye, Qing Srivastava, Pranay Al-Kuwari, Nasser Chen, Xiqun Neural Regen Res Research Article Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF(V600E) has also been implicated in neurodegeneration. The present study aims to characterize BRAF(V600E) during cell death and proliferation of three major cell types of the central nervous system: neurons, astrocytes, and microglia. Multiple primary cultures (primary cortical mixed culture) and cell lines of glial cells (BV2) and neurons (SH-SY5Y) were employed. BRAF(V600E) and BRAF(WT) expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors (extracellular signal-regulated kinase 1/2 and JNK1/2) were achieved by siRNA. In astrocytes and microglia, BRAF(V600E) induces cell proliferation, and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase, but not c-Jun N-terminal kinase. Conditioned medium from BRAF(V600E)-expressing microglia induced neuronal death. In neuronal cells, BRAF(V600E) directly induces neuronal death, through c-Jun N-terminal kinase but not extracellular signal-regulated kinase. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells. Wolters Kluwer - Medknow 2022-11-25 /pmc/articles/PMC10075110/ /pubmed/36571370 http://dx.doi.org/10.4103/1673-5374.361516 Text en Copyright: © Neural Regeneration Research https://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
spellingShingle Research Article
Ye, Qing
Srivastava, Pranay
Al-Kuwari, Nasser
Chen, Xiqun
Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title_full Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title_fullStr Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title_full_unstemmed Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title_short Oncogenic BRAF(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase
title_sort oncogenic braf(v600e) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-jun n-terminal kinase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075110/
https://www.ncbi.nlm.nih.gov/pubmed/36571370
http://dx.doi.org/10.4103/1673-5374.361516
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