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Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577224/ https://www.ncbi.nlm.nih.gov/pubmed/34686346 http://dx.doi.org/10.1016/j.celrep.2021.109870 |
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author | Duan, Shanshan Moro, Loredana Qu, Rui Simoneschi, Daniele Cho, Hyunwoo Jiang, Shaowen Zhao, Huiyong Chang, Qing de Stanchina, Elisa Arbini, Arnaldo A. Pagano, Michele |
author_facet | Duan, Shanshan Moro, Loredana Qu, Rui Simoneschi, Daniele Cho, Hyunwoo Jiang, Shaowen Zhao, Huiyong Chang, Qing de Stanchina, Elisa Arbini, Arnaldo A. Pagano, Michele |
author_sort | Duan, Shanshan |
collection | PubMed |
description | FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(FBXO31) promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and −2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer. |
format | Online Article Text |
id | pubmed-8577224 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-85772242021-11-09 Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis Duan, Shanshan Moro, Loredana Qu, Rui Simoneschi, Daniele Cho, Hyunwoo Jiang, Shaowen Zhao, Huiyong Chang, Qing de Stanchina, Elisa Arbini, Arnaldo A. Pagano, Michele Cell Rep Article FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(FBXO31) promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and −2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer. 2021-10-19 /pmc/articles/PMC8577224/ /pubmed/34686346 http://dx.doi.org/10.1016/j.celrep.2021.109870 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Duan, Shanshan Moro, Loredana Qu, Rui Simoneschi, Daniele Cho, Hyunwoo Jiang, Shaowen Zhao, Huiyong Chang, Qing de Stanchina, Elisa Arbini, Arnaldo A. Pagano, Michele Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title | Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title_full | Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title_fullStr | Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title_full_unstemmed | Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title_short | Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis |
title_sort | loss of fbxo31-mediated degradation of dusp6 dysregulates erk and pi3k-akt signaling and promotes prostate tumorigenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577224/ https://www.ncbi.nlm.nih.gov/pubmed/34686346 http://dx.doi.org/10.1016/j.celrep.2021.109870 |
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