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The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300
Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required for generating new tissue in homeostatic maintenance and repair processes, whereas cancer stem...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678591/ https://www.ncbi.nlm.nih.gov/pubmed/31324005 http://dx.doi.org/10.3390/cancers11070962 |
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author | Lukaszewicz, Agnes I. Nguyen, Cu Melendez, Elizabeth Lin, David P. Teo, Jia-Ling Lai, Keane K. Y. Huttner, Wieland B. Shi, Song-Hai Kahn, Michael |
author_facet | Lukaszewicz, Agnes I. Nguyen, Cu Melendez, Elizabeth Lin, David P. Teo, Jia-Ling Lai, Keane K. Y. Huttner, Wieland B. Shi, Song-Hai Kahn, Michael |
author_sort | Lukaszewicz, Agnes I. |
collection | PubMed |
description | Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required for generating new tissue in homeostatic maintenance and repair processes, whereas cancer stem cells (CSCs) favor symmetric divisions. We have previously proposed that differential β-catenin modulation of transcriptional activity via selective interaction with either the Kat3 coactivator CBP or its closely related paralog p300, regulates symmetric versus asymmetric division in SSCs and CSCs. We have previously demonstrated that SSCs that divide asymmetrically per force retain one of the dividing daughter cells in the stem cell niche, even when treated with specific CBP/β-catenin antagonists, whereas CSCs can be removed from their niche via forced stochastic symmetric differentiative divisions. We now demonstrate that loss of p73 in early corticogenesis biases β-catenin Kat3 coactivator usage and enhances β-catenin/CBP transcription at the expense of β-catenin/p300 transcription. Biased β-catenin coactivator usage has dramatic consequences on the mode of division of neural stem cells (NSCs), but not neurogenic progenitors. The observed increase in symmetric divisions due to enhanced β-catenin/CBP interaction and transcription leads to an immediate increase in NSC symmetric differentiative divisions. Moreover, we demonstrate for the first time that the complex phenotype caused by the loss of p73 can be rescued in utero by treatment with the small-molecule-specific CBP/β-catenin antagonist ICG-001. Taken together, our results demonstrate the causal relationship between the choice of β-catenin Kat3 coactivator and the mode of stem cell division. |
format | Online Article Text |
id | pubmed-6678591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66785912019-08-19 The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 Lukaszewicz, Agnes I. Nguyen, Cu Melendez, Elizabeth Lin, David P. Teo, Jia-Ling Lai, Keane K. Y. Huttner, Wieland B. Shi, Song-Hai Kahn, Michael Cancers (Basel) Article Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required for generating new tissue in homeostatic maintenance and repair processes, whereas cancer stem cells (CSCs) favor symmetric divisions. We have previously proposed that differential β-catenin modulation of transcriptional activity via selective interaction with either the Kat3 coactivator CBP or its closely related paralog p300, regulates symmetric versus asymmetric division in SSCs and CSCs. We have previously demonstrated that SSCs that divide asymmetrically per force retain one of the dividing daughter cells in the stem cell niche, even when treated with specific CBP/β-catenin antagonists, whereas CSCs can be removed from their niche via forced stochastic symmetric differentiative divisions. We now demonstrate that loss of p73 in early corticogenesis biases β-catenin Kat3 coactivator usage and enhances β-catenin/CBP transcription at the expense of β-catenin/p300 transcription. Biased β-catenin coactivator usage has dramatic consequences on the mode of division of neural stem cells (NSCs), but not neurogenic progenitors. The observed increase in symmetric divisions due to enhanced β-catenin/CBP interaction and transcription leads to an immediate increase in NSC symmetric differentiative divisions. Moreover, we demonstrate for the first time that the complex phenotype caused by the loss of p73 can be rescued in utero by treatment with the small-molecule-specific CBP/β-catenin antagonist ICG-001. Taken together, our results demonstrate the causal relationship between the choice of β-catenin Kat3 coactivator and the mode of stem cell division. MDPI 2019-07-09 /pmc/articles/PMC6678591/ /pubmed/31324005 http://dx.doi.org/10.3390/cancers11070962 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lukaszewicz, Agnes I. Nguyen, Cu Melendez, Elizabeth Lin, David P. Teo, Jia-Ling Lai, Keane K. Y. Huttner, Wieland B. Shi, Song-Hai Kahn, Michael The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title | The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title_full | The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title_fullStr | The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title_full_unstemmed | The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title_short | The Mode of Stem Cell Division Is Dependent on the Differential Interaction of β-Catenin with the Kat3 Coactivators CBP or p300 |
title_sort | mode of stem cell division is dependent on the differential interaction of β-catenin with the kat3 coactivators cbp or p300 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678591/ https://www.ncbi.nlm.nih.gov/pubmed/31324005 http://dx.doi.org/10.3390/cancers11070962 |
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