An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
Nagy, Z
Seneviratne, JA
Kanikevich, M
Chang, W
Mayoh, C
Venkat, P
Du, Y
Jiang, C
Salib, A
Koach, J
Carter, DR
Mittra, R
Liu, T
Parker, MW
Cheung, BB
Marshall, GM
- Publisher:
- Nature Research
- Publication Type:
- Journal Article
- Citation:
- Nature Communications, 2021, 12, (1), pp. 1-20
- Issue Date:
- 2021-03-25
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Nagy, Z | |
dc.contributor.author | Seneviratne, JA | |
dc.contributor.author | Kanikevich, M | |
dc.contributor.author | Chang, W | |
dc.contributor.author | Mayoh, C | |
dc.contributor.author | Venkat, P | |
dc.contributor.author | Du, Y | |
dc.contributor.author | Jiang, C | |
dc.contributor.author | Salib, A | |
dc.contributor.author | Koach, J | |
dc.contributor.author | Carter, DR | |
dc.contributor.author | Mittra, R | |
dc.contributor.author | Liu, T | |
dc.contributor.author | Parker, MW | |
dc.contributor.author | Cheung, BB | |
dc.contributor.author | Marshall, GM | |
dc.date.accessioned | 2022-03-09T23:50:40Z | |
dc.date.available | 2021-02-23 | |
dc.date.available | 2022-03-09T23:50:40Z | |
dc.date.issued | 2021-03-25 | |
dc.identifier.citation | Nature Communications, 2021, 12, (1), pp. 1-20 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/10453/155123 | |
dc.description.abstract | 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. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | Nature Research | |
dc.relation.ispartof | Nature Communications | |
dc.relation.isbasedon | 10.1038/s41467-021-22143-x | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Carcinogenesis | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Cell Survival | |
dc.subject.mesh | Chromosomes, Human, Pair 17 | |
dc.subject.mesh | DNA Copy Number Variations | |
dc.subject.mesh | HEK293 Cells | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | N-Myc Proto-Oncogene Protein | |
dc.subject.mesh | Neuroblastoma | |
dc.subject.mesh | Nuclear Proteins | |
dc.subject.mesh | Prognosis | |
dc.subject.mesh | RNA Interference | |
dc.subject.mesh | RNA, Small Interfering | |
dc.subject.mesh | RNA-Binding Proteins | |
dc.subject.mesh | Transcription Factors | |
dc.subject.mesh | Transcription, Genetic | |
dc.subject.mesh | Transcriptional Activation | |
dc.subject.mesh | Ubiquitin-Specific Proteases | |
dc.subject.mesh | Ubiquitination | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Chromosomes, Human, Pair 17 | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Neuroblastoma | |
dc.subject.mesh | RNA-Binding Proteins | |
dc.subject.mesh | Nuclear Proteins | |
dc.subject.mesh | Transcription Factors | |
dc.subject.mesh | RNA, Small Interfering | |
dc.subject.mesh | Prognosis | |
dc.subject.mesh | Cell Survival | |
dc.subject.mesh | Transcription, Genetic | |
dc.subject.mesh | RNA Interference | |
dc.subject.mesh | Ubiquitination | |
dc.subject.mesh | Transcriptional Activation | |
dc.subject.mesh | DNA Copy Number Variations | |
dc.subject.mesh | HEK293 Cells | |
dc.subject.mesh | Ubiquitin-Specific Proteases | |
dc.subject.mesh | Carcinogenesis | |
dc.subject.mesh | N-Myc Proto-Oncogene Protein | |
dc.title | An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability | |
dc.type | Journal Article | |
utslib.citation.volume | 12 | |
utslib.location.activity | England | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | /University of Technology Sydney/Strength - CHT - Health Technologies | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
pubs.organisational-group | /University of Technology Sydney/Centre for Health Technologies (CHT) | |
utslib.copyright.status | open_access | * |
pubs.consider-herdc | false | |
dc.date.updated | 2022-03-09T23:50:33Z | |
pubs.issue | 1 | |
pubs.publication-status | Published | |
pubs.volume | 12 | |
utslib.citation.issue | 1 |
Abstract:
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.
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