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Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage

Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p...

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Autores principales: Lin, Y-C, Chen, Y-N, Lin, K-F, Wang, F-F, Chou, T-Y, Chen, M-Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040702/
https://www.ncbi.nlm.nih.gov/pubmed/24407240
http://dx.doi.org/10.1038/cddis.2013.527
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author Lin, Y-C
Chen, Y-N
Lin, K-F
Wang, F-F
Chou, T-Y
Chen, M-Y
author_facet Lin, Y-C
Chen, Y-N
Lin, K-F
Wang, F-F
Chou, T-Y
Chen, M-Y
author_sort Lin, Y-C
collection PubMed
description Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p21-mediated PLK1 repression. Chromatin immunoprecipitation showed that cyclin-dependent kinase 2 (CDK2) associated with the CCAAT box-containing region of PLK1 promoter in unstressed cells, whereas adriamycin (ADR) induced the recruitment of p21 with a concomitant reduction in the occupancy of CDK2 in this region. Expression of p21 inhibited the interaction between CDK2 and the nuclear factor YA (NF-YA) subunit of the CCAAT box-binding transcription factor NF-Y. A mutant p21 that is defective in CDK2 binding was unable to disrupt the CDK2–NF-YA interaction or suppress PLK1 transcription. Co-immunoprecipitation experiments demonstrated the interaction between NF-YA and p21, and in vitro assays showed that p21 could directly bind to NF-YA. Knockdown of NF-YA decreased the amount of PLK1 promoter-associated p21 and abolished p21-mediated PLK1 repression in cells treated with ADR. Depletion of NF-YA diminished the p53-regulated transcriptional activation and suppressed the p53-mediated protection from mitotic death after DNA damage, and these effects of NF-YA deletion were alleviated by PLK1 depletion. Our findings have uncovered a novel p21/NF-YA/PLK1 axis critical for maintaining the checkpoint function of p53 to prevent mitotic death in the DNA damage-induced response.
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spelling pubmed-40407022014-06-02 Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage Lin, Y-C Chen, Y-N Lin, K-F Wang, F-F Chou, T-Y Chen, M-Y Cell Death Dis Original Article Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p21-mediated PLK1 repression. Chromatin immunoprecipitation showed that cyclin-dependent kinase 2 (CDK2) associated with the CCAAT box-containing region of PLK1 promoter in unstressed cells, whereas adriamycin (ADR) induced the recruitment of p21 with a concomitant reduction in the occupancy of CDK2 in this region. Expression of p21 inhibited the interaction between CDK2 and the nuclear factor YA (NF-YA) subunit of the CCAAT box-binding transcription factor NF-Y. A mutant p21 that is defective in CDK2 binding was unable to disrupt the CDK2–NF-YA interaction or suppress PLK1 transcription. Co-immunoprecipitation experiments demonstrated the interaction between NF-YA and p21, and in vitro assays showed that p21 could directly bind to NF-YA. Knockdown of NF-YA decreased the amount of PLK1 promoter-associated p21 and abolished p21-mediated PLK1 repression in cells treated with ADR. Depletion of NF-YA diminished the p53-regulated transcriptional activation and suppressed the p53-mediated protection from mitotic death after DNA damage, and these effects of NF-YA deletion were alleviated by PLK1 depletion. Our findings have uncovered a novel p21/NF-YA/PLK1 axis critical for maintaining the checkpoint function of p53 to prevent mitotic death in the DNA damage-induced response. Nature Publishing Group 2014-01 2014-01-09 /pmc/articles/PMC4040702/ /pubmed/24407240 http://dx.doi.org/10.1038/cddis.2013.527 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Lin, Y-C
Chen, Y-N
Lin, K-F
Wang, F-F
Chou, T-Y
Chen, M-Y
Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title_full Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title_fullStr Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title_full_unstemmed Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title_short Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
title_sort association of p21 with nf-ya suppresses the expression of polo-like kinase 1 and prevents mitotic death in response to dna damage
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040702/
https://www.ncbi.nlm.nih.gov/pubmed/24407240
http://dx.doi.org/10.1038/cddis.2013.527
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