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Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer

BACKGROUND: Both mTOR and Skp2 play critical roles in gastric cancer (GC) tumorigenesis. However, potential mechanisms for the association between these two proteins remains unidentified. METHODS: The regulatory role for mTORC1 in Skp2 stability was tested using ubiquitination assay. The functions o...

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Autores principales: Geng, Qirong, Liu, Jianjun, Gong, Zhaohui, Chen, Shangxiang, Chen, Shuai, Li, Xiaoxing, Lu, Yue, Zhu, Xiaofeng, Lin, Hui-kuan, Xu, Dazhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407005/
https://www.ncbi.nlm.nih.gov/pubmed/28446188
http://dx.doi.org/10.1186/s12943-017-0649-0
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author Geng, Qirong
Liu, Jianjun
Gong, Zhaohui
Chen, Shangxiang
Chen, Shuai
Li, Xiaoxing
Lu, Yue
Zhu, Xiaofeng
Lin, Hui-kuan
Xu, Dazhi
author_facet Geng, Qirong
Liu, Jianjun
Gong, Zhaohui
Chen, Shangxiang
Chen, Shuai
Li, Xiaoxing
Lu, Yue
Zhu, Xiaofeng
Lin, Hui-kuan
Xu, Dazhi
author_sort Geng, Qirong
collection PubMed
description BACKGROUND: Both mTOR and Skp2 play critical roles in gastric cancer (GC) tumorigenesis. However, potential mechanisms for the association between these two proteins remains unidentified. METHODS: The regulatory role for mTORC1 in Skp2 stability was tested using ubiquitination assay. The functions of p-Skp2 (phosphorylation of Skp2) were studied in vitro and in vivo. Expression of p-Skp2 and p-mTOR (phosphorylation of mTOR) were shown in GC lines and in 169 human primary GC tissues. RESULTS: mTORC1 can directly interact with Skp2 and phosphorylated Skp2 at Ser64, which sequentially protect Skp2 from ubiquitination and degradation. Furthermore, the phospho-deficient p-Skp2 (S64) mutant significantly suppresses GC cell proliferation and tumorigenesis. The expression of p-Skp2 was associated with p-mTOR in GC cell lines and tissues. Interestingly, the combination of p-Skp2 and p-mTOR was a better predictor of survival than either factor alone. CONCLUSION: The mTORC1 function to regulate Skp2 by Ser64 phosphorylation may represent an oncogenic event in GC tumorigenesis. Moreover, our study also indicates that Skp2 Ser64 expression is a potential indicator in the treatment of GC patients using mTORC1 inhibitor. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0649-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-54070052017-05-02 Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer Geng, Qirong Liu, Jianjun Gong, Zhaohui Chen, Shangxiang Chen, Shuai Li, Xiaoxing Lu, Yue Zhu, Xiaofeng Lin, Hui-kuan Xu, Dazhi Mol Cancer Research BACKGROUND: Both mTOR and Skp2 play critical roles in gastric cancer (GC) tumorigenesis. However, potential mechanisms for the association between these two proteins remains unidentified. METHODS: The regulatory role for mTORC1 in Skp2 stability was tested using ubiquitination assay. The functions of p-Skp2 (phosphorylation of Skp2) were studied in vitro and in vivo. Expression of p-Skp2 and p-mTOR (phosphorylation of mTOR) were shown in GC lines and in 169 human primary GC tissues. RESULTS: mTORC1 can directly interact with Skp2 and phosphorylated Skp2 at Ser64, which sequentially protect Skp2 from ubiquitination and degradation. Furthermore, the phospho-deficient p-Skp2 (S64) mutant significantly suppresses GC cell proliferation and tumorigenesis. The expression of p-Skp2 was associated with p-mTOR in GC cell lines and tissues. Interestingly, the combination of p-Skp2 and p-mTOR was a better predictor of survival than either factor alone. CONCLUSION: The mTORC1 function to regulate Skp2 by Ser64 phosphorylation may represent an oncogenic event in GC tumorigenesis. Moreover, our study also indicates that Skp2 Ser64 expression is a potential indicator in the treatment of GC patients using mTORC1 inhibitor. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0649-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-04-26 /pmc/articles/PMC5407005/ /pubmed/28446188 http://dx.doi.org/10.1186/s12943-017-0649-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Geng, Qirong
Liu, Jianjun
Gong, Zhaohui
Chen, Shangxiang
Chen, Shuai
Li, Xiaoxing
Lu, Yue
Zhu, Xiaofeng
Lin, Hui-kuan
Xu, Dazhi
Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title_full Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title_fullStr Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title_full_unstemmed Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title_short Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
title_sort phosphorylation by mtorc1 stablizes skp2 and regulates its oncogenic function in gastric cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407005/
https://www.ncbi.nlm.nih.gov/pubmed/28446188
http://dx.doi.org/10.1186/s12943-017-0649-0
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