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An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromoso...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994381/ https://www.ncbi.nlm.nih.gov/pubmed/33767157 http://dx.doi.org/10.1038/s41467-021-22143-x |
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author | Nagy, Zsuzsanna Seneviratne, Janith A. Kanikevich, Maxwell Chang, William Mayoh, Chelsea Venkat, Pooja Du, Yanhua Jiang, Cizhong Salib, Alice Koach, Jessica Carter, Daniel R. Mittra, Rituparna Liu, Tao Parker, Michael W. Cheung, Belamy B. Marshall, Glenn M. |
author_facet | Nagy, Zsuzsanna Seneviratne, Janith A. Kanikevich, Maxwell Chang, William Mayoh, Chelsea Venkat, Pooja Du, Yanhua Jiang, Cizhong Salib, Alice Koach, Jessica Carter, Daniel R. Mittra, Rituparna Liu, Tao Parker, Michael W. Cheung, Belamy B. Marshall, Glenn M. |
author_sort | Nagy, Zsuzsanna |
collection | PubMed |
description | To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies. |
format | Online Article Text |
id | pubmed-7994381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79943812021-04-16 An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability Nagy, Zsuzsanna Seneviratne, Janith A. Kanikevich, Maxwell Chang, William Mayoh, Chelsea Venkat, Pooja Du, Yanhua Jiang, Cizhong Salib, Alice Koach, Jessica Carter, Daniel R. Mittra, Rituparna Liu, Tao Parker, Michael W. Cheung, Belamy B. Marshall, Glenn M. Nat Commun Article To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies. Nature Publishing Group UK 2021-03-25 /pmc/articles/PMC7994381/ /pubmed/33767157 http://dx.doi.org/10.1038/s41467-021-22143-x Text en © The Author(s) 2021 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 Nagy, Zsuzsanna Seneviratne, Janith A. Kanikevich, Maxwell Chang, William Mayoh, Chelsea Venkat, Pooja Du, Yanhua Jiang, Cizhong Salib, Alice Koach, Jessica Carter, Daniel R. Mittra, Rituparna Liu, Tao Parker, Michael W. Cheung, Belamy B. Marshall, Glenn M. An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title_full | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title_fullStr | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title_full_unstemmed | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title_short | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability |
title_sort | alyref-mycn coactivator complex drives neuroblastoma tumorigenesis through effects on usp3 and mycn stability |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994381/ https://www.ncbi.nlm.nih.gov/pubmed/33767157 http://dx.doi.org/10.1038/s41467-021-22143-x |
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