title: TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation.
abstract: 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.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Huey-Huey
authors.initials: HH
authors.lastname: Chua
authors.affiliation: Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Weng
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Te-Huei
authors.initials: TH
authors.lastname: Yeh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099177:Tsg101 Protein
keywords: TSG101; alternative splicing; nasopharyngeal carcinoma; tumorigenesis; ubiquitination
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