TSGΔ154-1054 splice variant increases TSG101 oncogenicity by inhibiting its E3-ligase-mediated proteasomal degradation
Journal
Oncotarget
Journal Volume
7
Journal Issue
7
Pages
8240-8252
Date Issued
2016
Author(s)
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.
SDGs
Other Subjects
messenger RNA; oncoprotein; protein MDM2; protein p53; TSG101 associated E3 ligase; tumor susceptibility gene 101; ubiquitin protein ligase E3; unclassified drug; DNA binding protein; ESCRT protein; messenger RNA; protein binding; transcription factor; tumor susceptibility gene 101 protein; ubiquitin; ubiquitin protein ligase; animal experiment; animal model; animal tissue; Article; binding competition; breast cancer; breast cancer cell line; carcinogenicity; cell proliferation; clonogenesis; controlled study; gene expression regulation; genetic variability; human; human cell; human tissue; mouse; nonhuman; protein degradation; protein processing; protein protein interaction; protein stability; RNA splicing; Saos 2 cell line; TSG101 gene; tumor suppressor gene; tumor xenograft; U2OS cell line; ubiquitination; amino acid sequence; animal; apoptosis; Bagg albino mouse; cell transformation; drug screening; female; flow cytometry; genetics; immunoprecipitation; metabolism; neoplasm; Northern blotting; nude mouse; pathology; protein degradation; protein transport; real time polymerase chain reaction; reverse transcription polymerase chain reaction; RNA splicing; sequence homology; tumor cell culture; Western blotting; Amino Acid Sequence; Animals; Apoptosis; Blotting, Northern; Blotting, Western; Cell Proliferation; Cell Transformation, Neoplastic; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; Female; Flow Cytometry; Humans; Immunoprecipitation; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Protein Binding; Protein Transport; Proteolysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; RNA, Messenger; Sequence Homology, Amino Acid; Transcription Factors; Tumor Cells, Cultured; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Xenograft Model Antitumor Assays
Publisher
Impact Journals LLC
Type
journal article