Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis.

Cheung, BB; Mittra, R; Murray, J; Wang, Q; Seneviratne, JA; Raipuria, M; Wong, IPL; Restuccia, D; Gifford, A; Salib, A; Sutton, S; Huang, L; Ferdowsi, PV; Tsang, J; Sekyere, E; Mayoh, C; Luo, L; Brown, DL; Stow, JL; Zhu, S; Young, RJ; Solomon, BJ; Chappaz, S; Kile, B; Kueh, A; Herold, MJ; Hilton, DJ; Liu, T; Norris, MD; Haber, M; Carter, DR; Parker, MW; Marshall, GM

Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis.

Cheung, BB Mittra, R Murray, J Wang, Q Seneviratne, JA Raipuria, M Wong, IPL Restuccia, D Gifford, A Salib, A Sutton, S Huang, L Ferdowsi, PV Tsang, J Sekyere, E Mayoh, C Luo, L Brown, DL Stow, JL Zhu, S Young, RJ Solomon, BJ Chappaz, S Kile, B Kueh, A Herold, MJ Hilton, DJ Liu, T Norris, MD Haber, M Carter, DR Parker, MW Marshall, GM

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Commun Biol, 2024, 7, (1), pp. 1322
Issue Date:: 2024-10-14

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Field	Value	Language
dc.contributor.author	Cheung, BB
dc.contributor.author	Mittra, R
dc.contributor.author	Murray, J
dc.contributor.author	Wang, Q
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Raipuria, M
dc.contributor.author	Wong, IPL
dc.contributor.author	Restuccia, D
dc.contributor.author	Gifford, A
dc.contributor.author	Salib, A
dc.contributor.author	Sutton, S
dc.contributor.author	Huang, L
dc.contributor.author	Ferdowsi, PV
dc.contributor.author	Tsang, J
dc.contributor.author	Sekyere, E
dc.contributor.author	Mayoh, C
dc.contributor.author	Luo, L
dc.contributor.author	Brown, DL
dc.contributor.author	Stow, JL
dc.contributor.author	Zhu, S
dc.contributor.author	Young, RJ
dc.contributor.author	Solomon, BJ
dc.contributor.author	Chappaz, S
dc.contributor.author	Kile, B
dc.contributor.author	Kueh, A
dc.contributor.author	Herold, MJ
dc.contributor.author	Hilton, DJ
dc.contributor.author	Liu, T
dc.contributor.author	Norris, MD
dc.contributor.author	Haber, M
dc.contributor.author	Carter, DR
dc.contributor.author	Parker, MW
dc.contributor.author	Marshall, GM
dc.date.accessioned	2024-12-02T01:08:18Z
dc.date.available	2024-09-16
dc.date.available	2024-12-02T01:08:18Z
dc.date.issued	2024-10-14
dc.identifier.citation	Commun Biol, 2024, 7, (1), pp. 1322
dc.identifier.issn	2399-3642
dc.identifier.issn	2399-3642
dc.identifier.uri	http://hdl.handle.net/10453/182208
dc.description.abstract	MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121WT) gene mutated to RNFM158R associated with heritable loss of tumorigenicity. While the RNF121WT protein localised predominantly to the cis-Golgi Complex, the RNF121M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121WT transmembrane Helix 5. RNF121WT directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.
dc.format	Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation.ispartof	Commun Biol
dc.relation.isbasedon	10.1038/s42003-024-06899-8
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Golgi Apparatus
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Golgi Apparatus
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Golgi Apparatus
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.title	Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis.
dc.type	Journal Article
utslib.citation.volume	7
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/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2024-12-02T01:08:12Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	7
utslib.citation.issue	1

Abstract:

MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121WT) gene mutated to RNFM158R associated with heritable loss of tumorigenicity. While the RNF121WT protein localised predominantly to the cis-Golgi Complex, the RNF121M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121WT transmembrane Helix 5. RNF121WT directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/182208