TSG&#916;154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation.

Chua, Huey-Huey; Huang, Chiun-Sheng; Weng, Pei-Lun; Yeh, Te-Huei

TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation.

Chua, Huey-Huey; Huang, Chiun-Sheng; Weng, Pei-Lun; Yeh, Te-Huei.

Afiliación

Chua HH; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Huang CS; Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Weng PL; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Yeh TH; Department of Otolaryngology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Oncotarget ; 7(7): 8240-52, 2016 Feb 16.

Article en En | MEDLINE | ID: mdl-26811492

RESUMEN

Tumor susceptibility gene 101 (TSG101) elicits an array of cellular functions, including promoting cytokinesis, cell cycle progression and proliferation, as well as facilitating endosomal trafficking and viral budding. TSG101 protein is highly and aberrantly expressed in various human cancers. Specifically, a TSG101 splicing variant missing nucleotides 154 to 1054 (TSGΔ154-1054), which is linked to progressive tumor-stage and metastasis, has puzzled investigators for more than a decade. TSG101-associated E3 ligase (Tal)- and MDM2-mediated proteasomal degradation are the two major routes for posttranslational regulation of the total amount of TSG101. We reveal that overabundance of TSG101 results from TSGΔ154-1054 stabilizing the TSG101 protein by competitively binding to Tal, but not MDM2, thereby perturbing the Tal interaction with TSG101 and impeding subsequent polyubiquitination and proteasomal degradation of TSG101. TSGΔ154-1054 therefore specifically enhances TSG101-stimulated cell proliferation, clonogenicity, and tumor growth in nude mice. This finding shows the functional significance of TSGΔ154-1054 in preventing the ubiquitin-proteasome proteolysis of TSG101, which increases tumor malignancy and hints at its potential as a therapeutic target in cancer treatment.

Asunto(s)

Transformación Celular Neoplásica/patología; Proteínas de Unión al ADN/genética; Complejos de Clasificación Endosomal Requeridos para el Transporte/genética; Neoplasias/patología; Empalme del ARN/genética; Factores de Transcripción/genética; Ubiquitina-Proteína Ligasas/metabolismo; Ubiquitina/metabolismo; Secuencia de Aminoácidos; Animales; Apoptosis; Northern Blotting; Western Blotting; Proliferación Celular; Transformación Celular Neoplásica/genética; Transformación Celular Neoplásica/metabolismo; Proteínas de Unión al ADN/metabolismo; Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo; Femenino; Citometría de Flujo; Humanos; Inmunoprecipitación; Ratones; Ratones Endogámicos BALB C; Ratones Desnudos; Neoplasias/genética; Neoplasias/metabolismo; Unión Proteica; Transporte de Proteínas; Proteolisis; ARN Mensajero/genética; Reacción en Cadena en Tiempo Real de la Polimerasa; Reacción en Cadena de la Polimerasa de Transcriptasa Inversa; Homología de Secuencia de Aminoácido; Factores de Transcripción/metabolismo; Células Tumorales Cultivadas; Ubiquitina-Proteína Ligasas/genética; Ubiquitinación; Ensayos Antitumor por Modelo de Xenoinjerto

Palabras clave

TSG101; alternative splicing; nasopharyngeal carcinoma; tumorigenesis; ubiquitination

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Transformación Celular Neoplásica / Empalme del ARN / Ubiquitina / Ubiquitina-Proteína Ligasas / Proteínas de Unión al ADN / Complejos de Clasificación Endosomal Requeridos para el Transporte / Neoplasias Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Estados Unidos

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