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GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival
Claspin is essential for activating the DNA damage checkpoint effector kinase Chk1, a target in oncotherapy. Claspin functions are tightly correlated to Claspin protein stability, regulated by ubiquitin-dependent proteasomal degradation. Here we identify Glycogen Synthase Kinase 3-β (GSK3-β) as a ne...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721324/ https://www.ncbi.nlm.nih.gov/pubmed/31362447 http://dx.doi.org/10.3390/cancers11081073 |
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author | Cabrera, Elisa Raninga, Prahlad Khanna, Kum Kum Freire, Raimundo |
author_facet | Cabrera, Elisa Raninga, Prahlad Khanna, Kum Kum Freire, Raimundo |
author_sort | Cabrera, Elisa |
collection | PubMed |
description | Claspin is essential for activating the DNA damage checkpoint effector kinase Chk1, a target in oncotherapy. Claspin functions are tightly correlated to Claspin protein stability, regulated by ubiquitin-dependent proteasomal degradation. Here we identify Glycogen Synthase Kinase 3-β (GSK3-β) as a new regulator of Claspin stability. Interestingly, as Chk1, GSK3-β is a therapeutic target in cancer. GSK3-β inhibition or knockdown stabilizes Claspin, whereas a GSK3-β constitutively active form reduces Claspin protein levels by ubiquitination and proteasome-mediated degradation. Our results also suggest that GSK3-β modulates the interaction of Claspin with β-TrCP, a critical E3 ubiquitin ligase that regulates Claspin stability. Importantly, GSK3-β knock down increases Chk1 activation in response to DNA damage in a Claspin-dependent manner. Therefore, Chk1 activation could be a pro-survival mechanism that becomes activated upon GSK3-β inhibition. Importantly, treating triple negative breast cancer cell lines with Chk1 or GSK3-β inhibitors alone or in combination, demonstrates that Chk1/GSK3-β double inhibition restrains cell growth and triggers more apoptosis compared to individual treatments, thereby revealing novel possibilities for a combination therapy for cancer. |
format | Online Article Text |
id | pubmed-6721324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67213242019-09-10 GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival Cabrera, Elisa Raninga, Prahlad Khanna, Kum Kum Freire, Raimundo Cancers (Basel) Article Claspin is essential for activating the DNA damage checkpoint effector kinase Chk1, a target in oncotherapy. Claspin functions are tightly correlated to Claspin protein stability, regulated by ubiquitin-dependent proteasomal degradation. Here we identify Glycogen Synthase Kinase 3-β (GSK3-β) as a new regulator of Claspin stability. Interestingly, as Chk1, GSK3-β is a therapeutic target in cancer. GSK3-β inhibition or knockdown stabilizes Claspin, whereas a GSK3-β constitutively active form reduces Claspin protein levels by ubiquitination and proteasome-mediated degradation. Our results also suggest that GSK3-β modulates the interaction of Claspin with β-TrCP, a critical E3 ubiquitin ligase that regulates Claspin stability. Importantly, GSK3-β knock down increases Chk1 activation in response to DNA damage in a Claspin-dependent manner. Therefore, Chk1 activation could be a pro-survival mechanism that becomes activated upon GSK3-β inhibition. Importantly, treating triple negative breast cancer cell lines with Chk1 or GSK3-β inhibitors alone or in combination, demonstrates that Chk1/GSK3-β double inhibition restrains cell growth and triggers more apoptosis compared to individual treatments, thereby revealing novel possibilities for a combination therapy for cancer. MDPI 2019-07-29 /pmc/articles/PMC6721324/ /pubmed/31362447 http://dx.doi.org/10.3390/cancers11081073 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cabrera, Elisa Raninga, Prahlad Khanna, Kum Kum Freire, Raimundo GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title | GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title_full | GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title_fullStr | GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title_full_unstemmed | GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title_short | GSK3-β Stimulates Claspin Degradation via β-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival |
title_sort | gsk3-β stimulates claspin degradation via β-trcp ubiquitin ligase and alters cancer cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721324/ https://www.ncbi.nlm.nih.gov/pubmed/31362447 http://dx.doi.org/10.3390/cancers11081073 |
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