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Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2
Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 ca...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416753/ https://www.ncbi.nlm.nih.gov/pubmed/28119415 http://dx.doi.org/10.1093/nar/gkx039 |
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author | Plotnik, Joshua P. Hollenhorst, Peter C. |
author_facet | Plotnik, Joshua P. Hollenhorst, Peter C. |
author_sort | Plotnik, Joshua P. |
collection | PubMed |
description | Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner. |
format | Online Article Text |
id | pubmed-5416753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54167532017-05-05 Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 Plotnik, Joshua P. Hollenhorst, Peter C. Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner. Oxford University Press 2017-05-05 2017-01-24 /pmc/articles/PMC5416753/ /pubmed/28119415 http://dx.doi.org/10.1093/nar/gkx039 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Plotnik, Joshua P. Hollenhorst, Peter C. Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title | Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title_full | Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title_fullStr | Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title_full_unstemmed | Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title_short | Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2 |
title_sort | interaction with zmynd11 mediates opposing roles of ras-responsive transcription factors ets1 and ets2 |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416753/ https://www.ncbi.nlm.nih.gov/pubmed/28119415 http://dx.doi.org/10.1093/nar/gkx039 |
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