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Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300
The E-protein transcription factors play essential roles in lymphopoiesis, with E12 and E47 (hereafter called E2A) being particularly important in B cell specification and maturation. The E2A gene is also involved in a chromosomal translocation that results in the leukemogenic oncoprotein E2A-PBX1....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066744/ https://www.ncbi.nlm.nih.gov/pubmed/24682819 http://dx.doi.org/10.1093/nar/gku206 |
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author | Denis, Christopher M. Langelaan, David N. Kirlin, Alyssa C. Chitayat, Seth Munro, Kim Spencer, Holly L. LeBrun, David P. Smith, Steven P. |
author_facet | Denis, Christopher M. Langelaan, David N. Kirlin, Alyssa C. Chitayat, Seth Munro, Kim Spencer, Holly L. LeBrun, David P. Smith, Steven P. |
author_sort | Denis, Christopher M. |
collection | PubMed |
description | The E-protein transcription factors play essential roles in lymphopoiesis, with E12 and E47 (hereafter called E2A) being particularly important in B cell specification and maturation. The E2A gene is also involved in a chromosomal translocation that results in the leukemogenic oncoprotein E2A-PBX1. The two activation domains of E2A, AD1 and AD2, display redundant, independent, and cooperative functions in a cell-dependent manner. AD1 of E2A functions by binding the transcriptional co-activator CBP/p300; this interaction is required in oncogenesis and occurs between the conserved ϕ-x-x-ϕ-ϕ motif in AD1 and the KIX domain of CBP/p300. However, co-activator recruitment by AD2 has not been characterized. Here, we demonstrate that the first of two conserved ϕ-x-x-ϕ-ϕ motifs within AD2 of E2A interacts at the same binding site on KIX as AD1. Mutagenesis uncovered a correspondence between the KIX-binding affinity of AD2 and transcriptional activation. Although AD2 is dispensable for oncogenesis, experimentally increasing the affinity of AD2 for KIX uncovered a latent potential to mediate immortalization of primary hematopoietic progenitors by E2A-PBX1. Our findings suggest that redundancy between the two E2A activation domains with respect to transcriptional activation and oncogenic function is mediated by binding to the same surface of the KIX domain of CBP/p300. |
format | Online Article Text |
id | pubmed-4066744 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40667442014-06-24 Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 Denis, Christopher M. Langelaan, David N. Kirlin, Alyssa C. Chitayat, Seth Munro, Kim Spencer, Holly L. LeBrun, David P. Smith, Steven P. Nucleic Acids Res Structural Biology The E-protein transcription factors play essential roles in lymphopoiesis, with E12 and E47 (hereafter called E2A) being particularly important in B cell specification and maturation. The E2A gene is also involved in a chromosomal translocation that results in the leukemogenic oncoprotein E2A-PBX1. The two activation domains of E2A, AD1 and AD2, display redundant, independent, and cooperative functions in a cell-dependent manner. AD1 of E2A functions by binding the transcriptional co-activator CBP/p300; this interaction is required in oncogenesis and occurs between the conserved ϕ-x-x-ϕ-ϕ motif in AD1 and the KIX domain of CBP/p300. However, co-activator recruitment by AD2 has not been characterized. Here, we demonstrate that the first of two conserved ϕ-x-x-ϕ-ϕ motifs within AD2 of E2A interacts at the same binding site on KIX as AD1. Mutagenesis uncovered a correspondence between the KIX-binding affinity of AD2 and transcriptional activation. Although AD2 is dispensable for oncogenesis, experimentally increasing the affinity of AD2 for KIX uncovered a latent potential to mediate immortalization of primary hematopoietic progenitors by E2A-PBX1. Our findings suggest that redundancy between the two E2A activation domains with respect to transcriptional activation and oncogenic function is mediated by binding to the same surface of the KIX domain of CBP/p300. Oxford University Press 2014-07-01 2014-03-20 /pmc/articles/PMC4066744/ /pubmed/24682819 http://dx.doi.org/10.1093/nar/gku206 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), 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 | Structural Biology Denis, Christopher M. Langelaan, David N. Kirlin, Alyssa C. Chitayat, Seth Munro, Kim Spencer, Holly L. LeBrun, David P. Smith, Steven P. Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title | Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title_full | Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title_fullStr | Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title_full_unstemmed | Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title_short | Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300 |
title_sort | functional redundancy between the transcriptional activation domains of e2a is mediated by binding to the kix domain of cbp/p300 |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066744/ https://www.ncbi.nlm.nih.gov/pubmed/24682819 http://dx.doi.org/10.1093/nar/gku206 |
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