TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation
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Huey-Huey Chua1,*, Chiun-Sheng Huang2,*, Pei-Lun Weng1, Te-Huei Yeh3
1Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
2Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
3Department of Otolaryngology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
*These authors have contributed equally to this work
Te-Huei Yeh, e-mail: [email protected]
Keywords: TSG101, alternative splicing, ubiquitination, tumorigenesis, nasopharyngeal carcinoma
Received: June 29, 2015 Accepted: January 12, 2016 Published: January 22, 2016
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.
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