Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma.

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-FBXW7? ...
and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7? in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7? significantly attenuated tumor growth. Meanwhile, FBXW7? reversed the oncogenic phenotype and the activation of the AKT/ERK/NF?B pathway induced by NOTCH1C1133Y mutation. FBXW7? 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 FBXW7? that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7? and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.
Mesh Terms:
Adult, Aged, Aged, 80 and over, Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Movement, Cell Proliferation, Endoplasmic Reticulum, F-Box-WD Repeat-Containing Protein 7, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Male, Mice, Nude, Middle Aged, Mouth Neoplasms, Mutation, NF-kappa B, Neoplasm Invasiveness, Oncogenes, Phenotype, Protein Binding, Protein Isoforms, Receptor, Notch1, Ubiquitination
Cell Death Dis
Date: Dec. 13, 2019
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