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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...

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Autores principales: Zheng, Yang, Song, An, Wang, Chundi, Zhang, Wei, Liang, Dong, Ding, Xu, Li, Gang, Zhang, Hongchuang, Du, Yifei, Zhou, Junbo, Wu, Heming, Wu, Yunong, Song, Xiaomeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426429/
https://www.ncbi.nlm.nih.gov/pubmed/32792479
http://dx.doi.org/10.1038/s41419-020-02873-4
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author Zheng, Yang
Song, An
Wang, Chundi
Zhang, Wei
Liang, Dong
Ding, Xu
Li, Gang
Zhang, Hongchuang
Zhang, Wei
Du, Yifei
Zhou, Junbo
Wu, Heming
Wu, Yunong
Song, Xiaomeng
author_facet Zheng, Yang
Song, An
Wang, Chundi
Zhang, Wei
Liang, Dong
Ding, Xu
Li, Gang
Zhang, Hongchuang
Zhang, Wei
Du, Yifei
Zhou, Junbo
Wu, Heming
Wu, Yunong
Song, Xiaomeng
author_sort Zheng, Yang
collection PubMed
description 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 NOTCH1(C1133Y) 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 NOTCH1(C1133Y) and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1(C1133Y) mutation. FBXW7β downregulated the stability of NOTCH1(C1133Y) 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 NOTCH1(C1133Y) protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.
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spelling pubmed-74264292020-08-18 Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma Zheng, Yang Song, An Wang, Chundi Zhang, Wei Liang, Dong Ding, Xu Li, Gang Zhang, Hongchuang Zhang, Wei Du, Yifei Zhou, Junbo Wu, Heming Wu, Yunong Song, Xiaomeng Cell Death Dis Article 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 NOTCH1(C1133Y) 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 NOTCH1(C1133Y) and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1(C1133Y) mutation. FBXW7β downregulated the stability of NOTCH1(C1133Y) 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 NOTCH1(C1133Y) protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy. Nature Publishing Group UK 2020-08-13 /pmc/articles/PMC7426429/ /pubmed/32792479 http://dx.doi.org/10.1038/s41419-020-02873-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zheng, Yang
Song, An
Wang, Chundi
Zhang, Wei
Liang, Dong
Ding, Xu
Li, Gang
Zhang, Hongchuang
Zhang, Wei
Du, Yifei
Zhou, Junbo
Wu, Heming
Wu, Yunong
Song, Xiaomeng
Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title_full Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title_fullStr Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title_full_unstemmed Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title_short Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
title_sort isoform specific fbxw7 mediates notch1 abruptex mutation c1133y deregulation in oral squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426429/
https://www.ncbi.nlm.nih.gov/pubmed/32792479
http://dx.doi.org/10.1038/s41419-020-02873-4
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