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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.
Afiliación
  • Nagy Z; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Seneviratne JA; School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia.
  • Kanikevich M; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Chang W; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Mayoh C; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Venkat P; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Du Y; School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia.
  • Jiang C; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Salib A; School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • Koach J; School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • Carter DR; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Mittra R; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Liu T; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • Parker MW; School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia.
  • Cheung BB; School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia.
  • Marshall GM; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
Nat Commun ; 12(1): 1881, 2021 03 25.
Article en En | MEDLINE | ID: mdl-33767157
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Proteínas de Unión al ARN / Carcinogénesis / Proteasas Ubiquitina-Específicas / Proteína Proto-Oncogénica N-Myc / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Proteínas de Unión al ARN / Carcinogénesis / Proteasas Ubiquitina-Específicas / Proteína Proto-Oncogénica N-Myc / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Australia