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ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation
The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell dif...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837758/ https://www.ncbi.nlm.nih.gov/pubmed/35149717 http://dx.doi.org/10.1038/s41598-022-06248-x |
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author | Azzarelli, Roberta McNally, Aoibheann Dell’Amico, Claudia Onorati, Marco Simons, Benjamin Philpott, Anna |
author_facet | Azzarelli, Roberta McNally, Aoibheann Dell’Amico, Claudia Onorati, Marco Simons, Benjamin Philpott, Anna |
author_sort | Azzarelli, Roberta |
collection | PubMed |
description | The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell differentiation is a potential new therapeutic approach for this devastating disease. ASCL1, a proneural transcription factor, plays a key role in normal brain development and is also expressed in a subset of GBM cells, but fails to engage a full differentiation programme in this context. Here, we investigated the barriers to ASCL1-driven differentiation in GBM stem cells. We see that ASCL1 is highly phosphorylated in GBM stem cells where its expression is compatible with cell proliferation. However, overexpression of a form of ASCL1 that cannot be phosphorylated on Serine–Proline sites drives GBM cells down a neuronal lineage and out of cell cycle more efficiently than its wild-type counterpart, an effect further enhanced by deletion of the inhibitor of differentiation ID2, indicating mechanisms to reverse the block to GBM cell differentiation. |
format | Online Article Text |
id | pubmed-8837758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88377582022-02-16 ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation Azzarelli, Roberta McNally, Aoibheann Dell’Amico, Claudia Onorati, Marco Simons, Benjamin Philpott, Anna Sci Rep Article The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell differentiation is a potential new therapeutic approach for this devastating disease. ASCL1, a proneural transcription factor, plays a key role in normal brain development and is also expressed in a subset of GBM cells, but fails to engage a full differentiation programme in this context. Here, we investigated the barriers to ASCL1-driven differentiation in GBM stem cells. We see that ASCL1 is highly phosphorylated in GBM stem cells where its expression is compatible with cell proliferation. However, overexpression of a form of ASCL1 that cannot be phosphorylated on Serine–Proline sites drives GBM cells down a neuronal lineage and out of cell cycle more efficiently than its wild-type counterpart, an effect further enhanced by deletion of the inhibitor of differentiation ID2, indicating mechanisms to reverse the block to GBM cell differentiation. Nature Publishing Group UK 2022-02-11 /pmc/articles/PMC8837758/ /pubmed/35149717 http://dx.doi.org/10.1038/s41598-022-06248-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Azzarelli, Roberta McNally, Aoibheann Dell’Amico, Claudia Onorati, Marco Simons, Benjamin Philpott, Anna ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title | ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title_full | ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title_fullStr | ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title_full_unstemmed | ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title_short | ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation |
title_sort | ascl1 phosphorylation and id2 upregulation are roadblocks to glioblastoma stem cell differentiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837758/ https://www.ncbi.nlm.nih.gov/pubmed/35149717 http://dx.doi.org/10.1038/s41598-022-06248-x |
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