Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
| Autor: | Yang Zheng, An Song, Chundi Wang, Wei Zhang, Dong Liang, Xu Ding, Gang Li, Hongchuang Zhang, Yifei Du, Junbo Zhou, Heming Wu, Yunong Wu, Xiaomeng Song |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Cancer Research F-Box-WD Repeat-Containing Protein 7 Ubiquitylation Endoplasmic Reticulum medicine.disease_cause 0302 clinical medicine Ubiquitin Cell Movement Protein Isoforms Receptor Notch1 Aged 80 and over Mutation biology lcsh:Cytology Oral cancer NF-kappa B Middle Aged Phenotype Ubiquitin ligase Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis embryonic structures Carcinoma Squamous Cell Female Mouth Neoplasms Protein Binding Adult Gene isoform MAP Kinase Signaling System Immunology Mice Nude Article 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor medicine Animals Humans Neoplasm Invasiveness lcsh:QH573-671 Protein kinase B Aged Cell Proliferation Ubiquitination Oncogenes Cell Biology Protein ubiquitination stomatognathic diseases 030104 developmental biology biology.protein Cancer research |
| Zdroj: | Cell Death and Disease, Vol 11, Iss 8, Pp 1-15 (2020) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Our group previously identified that the NOTCH1 Abruptex domain contains the most mutations in Chinese OSCC patients, including a hotspot mutation (C1133Y). FBXW7 is an E3 ubiquitin ligase that regulates a network of proteins, including NOTCH1, via degradation. In this study, we first described the co-localization of isoform specific FBXW7-FBXW7β and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7β in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1C1133Y mutation. FBXW7β downregulated the stability of NOTCH1C1133Y protein and promoted protein ubiquitination. This was the first time that we selected a NOTCH1 hotspot mutation detected in clinical samples and identified the function of FBXW7β that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7β and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy. |
| Databáze: | OpenAIRE |
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