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Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7
Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have gener...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413036/ https://www.ncbi.nlm.nih.gov/pubmed/18474632 http://dx.doi.org/10.1084/jem.20080277 |
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author | Thompson, Benjamin J. Jankovic, Vladimir Gao, Jie Buonamici, Silvia Vest, Alan Lee, Jennifer May Zavadil, Jiri Nimer, Stephen D. Aifantis, Iannis |
author_facet | Thompson, Benjamin J. Jankovic, Vladimir Gao, Jie Buonamici, Silvia Vest, Alan Lee, Jennifer May Zavadil, Jiri Nimer, Stephen D. Aifantis, Iannis |
author_sort | Thompson, Benjamin J. |
collection | PubMed |
description | Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7(−/−) HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7(−/−) progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7(−/−) HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional “signature” that is associated with the quiescent, self-renewing HSC phenotype. |
format | Text |
id | pubmed-2413036 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-24130362008-12-09 Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 Thompson, Benjamin J. Jankovic, Vladimir Gao, Jie Buonamici, Silvia Vest, Alan Lee, Jennifer May Zavadil, Jiri Nimer, Stephen D. Aifantis, Iannis J Exp Med Articles Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7(−/−) HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7(−/−) progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7(−/−) HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional “signature” that is associated with the quiescent, self-renewing HSC phenotype. The Rockefeller University Press 2008-06-09 /pmc/articles/PMC2413036/ /pubmed/18474632 http://dx.doi.org/10.1084/jem.20080277 Text en © 2008 Thompson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Articles Thompson, Benjamin J. Jankovic, Vladimir Gao, Jie Buonamici, Silvia Vest, Alan Lee, Jennifer May Zavadil, Jiri Nimer, Stephen D. Aifantis, Iannis Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title_full | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title_fullStr | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title_full_unstemmed | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title_short | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
title_sort | control of hematopoietic stem cell quiescence by the e3 ubiquitin ligase fbw7 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413036/ https://www.ncbi.nlm.nih.gov/pubmed/18474632 http://dx.doi.org/10.1084/jem.20080277 |
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