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Squamous differentiation requires G2/mitosis slippage to avoid apoptosis

The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here,...

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Autores principales: Sanz-Gómez, Natalia, de Pedro, Isabel, Ortigosa, Beatriz, Santamaría, David, Malumbres, Marcos, de Cárcer, Guillermo, Gandarillas, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370216/
https://www.ncbi.nlm.nih.gov/pubmed/32080348
http://dx.doi.org/10.1038/s41418-020-0515-2
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author Sanz-Gómez, Natalia
de Pedro, Isabel
Ortigosa, Beatriz
Santamaría, David
Malumbres, Marcos
de Cárcer, Guillermo
Gandarillas, Alberto
author_facet Sanz-Gómez, Natalia
de Pedro, Isabel
Ortigosa, Beatriz
Santamaría, David
Malumbres, Marcos
de Cárcer, Guillermo
Gandarillas, Alberto
author_sort Sanz-Gómez, Natalia
collection PubMed
description The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here, we show that inactivation of the mitotic kinases leading to polyploidy in vivo, produces a fully differentiated epithelium. Cells within the basal layer aberrantly differentiate and contain large or various nuclei. Freshly isolated KO cells were also differentiated and polyploid. However, sustained metaphase arrest downstream of the spindle anaphase checkpoint (SAC) due to abrogation of CDC20 (essential cofactor of anaphase-promoting complex), impaired squamous differentiation and resulted in apoptosis. Therefore, upon prolonged arrest keratinocytes need to slip beyond G2 or mitosis in order to initiate differentiation. The results altogether demonstrate that mitotic checkpoints drive squamous cell fate towards differentiation or apoptosis in response to genetic damage.
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spelling pubmed-73702162020-07-24 Squamous differentiation requires G2/mitosis slippage to avoid apoptosis Sanz-Gómez, Natalia de Pedro, Isabel Ortigosa, Beatriz Santamaría, David Malumbres, Marcos de Cárcer, Guillermo Gandarillas, Alberto Cell Death Differ Article The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here, we show that inactivation of the mitotic kinases leading to polyploidy in vivo, produces a fully differentiated epithelium. Cells within the basal layer aberrantly differentiate and contain large or various nuclei. Freshly isolated KO cells were also differentiated and polyploid. However, sustained metaphase arrest downstream of the spindle anaphase checkpoint (SAC) due to abrogation of CDC20 (essential cofactor of anaphase-promoting complex), impaired squamous differentiation and resulted in apoptosis. Therefore, upon prolonged arrest keratinocytes need to slip beyond G2 or mitosis in order to initiate differentiation. The results altogether demonstrate that mitotic checkpoints drive squamous cell fate towards differentiation or apoptosis in response to genetic damage. Nature Publishing Group UK 2020-02-20 2020-08 /pmc/articles/PMC7370216/ /pubmed/32080348 http://dx.doi.org/10.1038/s41418-020-0515-2 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sanz-Gómez, Natalia
de Pedro, Isabel
Ortigosa, Beatriz
Santamaría, David
Malumbres, Marcos
de Cárcer, Guillermo
Gandarillas, Alberto
Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title_full Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title_fullStr Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title_full_unstemmed Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title_short Squamous differentiation requires G2/mitosis slippage to avoid apoptosis
title_sort squamous differentiation requires g2/mitosis slippage to avoid apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370216/
https://www.ncbi.nlm.nih.gov/pubmed/32080348
http://dx.doi.org/10.1038/s41418-020-0515-2
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