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Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3
Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt’s lymphoma correlating with a muta...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808939/ https://www.ncbi.nlm.nih.gov/pubmed/33122824 http://dx.doi.org/10.1038/s41388-020-01532-4 |
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author | Yoshida, Akihiro Choi, Jaewoo Jin, Hong Ri Li, Yan Bajpai, Sagar Qie, Shuo Diehl, J. Alan |
author_facet | Yoshida, Akihiro Choi, Jaewoo Jin, Hong Ri Li, Yan Bajpai, Sagar Qie, Shuo Diehl, J. Alan |
author_sort | Yoshida, Akihiro |
collection | PubMed |
description | Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt’s lymphoma correlating with a mutation of Thr-283. However, the E3 ligase that regulates phosphorylated cyclin D3 and whether a stabilized, phosphorylation deficient mutant of cyclin D3, has oncogenic activity are undefined. We describe the identification of SCF-Fbxl8 as the E3 ligase for Thr-283 phosphorylated cyclin D3. SCF-Fbxl8 poly-ubiquitylates p-Thr-283 cyclin D3 targeting it to the proteasome. Functional investigation demonstrates that Fbxl8 antagonizes cell cycle progression, hematopoietic cell proliferation, and oncogene-induced transformation through degradation of cyclin D3, which is abolished by expression of cyclin D3T283A, a non-phosphorylatable mutant. Clinically, the expression of cyclin D3 is inversely correlated with the expression of Fbxl8 in lymphomas from human patients implicating Fbxl8 functions as a tumor suppressor. |
format | Online Article Text |
id | pubmed-7808939 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78089392021-01-21 Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 Yoshida, Akihiro Choi, Jaewoo Jin, Hong Ri Li, Yan Bajpai, Sagar Qie, Shuo Diehl, J. Alan Oncogene Article Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt’s lymphoma correlating with a mutation of Thr-283. However, the E3 ligase that regulates phosphorylated cyclin D3 and whether a stabilized, phosphorylation deficient mutant of cyclin D3, has oncogenic activity are undefined. We describe the identification of SCF-Fbxl8 as the E3 ligase for Thr-283 phosphorylated cyclin D3. SCF-Fbxl8 poly-ubiquitylates p-Thr-283 cyclin D3 targeting it to the proteasome. Functional investigation demonstrates that Fbxl8 antagonizes cell cycle progression, hematopoietic cell proliferation, and oncogene-induced transformation through degradation of cyclin D3, which is abolished by expression of cyclin D3T283A, a non-phosphorylatable mutant. Clinically, the expression of cyclin D3 is inversely correlated with the expression of Fbxl8 in lymphomas from human patients implicating Fbxl8 functions as a tumor suppressor. Nature Publishing Group UK 2020-10-29 2021 /pmc/articles/PMC7808939/ /pubmed/33122824 http://dx.doi.org/10.1038/s41388-020-01532-4 Text en © The Author(s), under exclusive licence to Springer Nature Limited 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 Yoshida, Akihiro Choi, Jaewoo Jin, Hong Ri Li, Yan Bajpai, Sagar Qie, Shuo Diehl, J. Alan Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title | Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title_full | Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title_fullStr | Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title_full_unstemmed | Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title_short | Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3 |
title_sort | fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin d3 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808939/ https://www.ncbi.nlm.nih.gov/pubmed/33122824 http://dx.doi.org/10.1038/s41388-020-01532-4 |
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