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Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells
Growth factor erv1-like (Gfer) is an evolutionarily conserved sulfhydryl oxidase that is enriched in embryonic and adult stem cells and plays an essential prosurvival role in pluripotent embryonic stem cells. Here we show that knockdown (KD) of Gfer in hematopoietic stem cells (HSCs) compromises the...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078070/ https://www.ncbi.nlm.nih.gov/pubmed/21346186 http://dx.doi.org/10.1091/mbc.E10-08-0723 |
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author | Teng, Ellen C. Todd, Lance R. Ribar, Thomas J. Lento, William Dimascio, Leah Means, Anthony R. Sankar, Uma |
author_facet | Teng, Ellen C. Todd, Lance R. Ribar, Thomas J. Lento, William Dimascio, Leah Means, Anthony R. Sankar, Uma |
author_sort | Teng, Ellen C. |
collection | PubMed |
description | Growth factor erv1-like (Gfer) is an evolutionarily conserved sulfhydryl oxidase that is enriched in embryonic and adult stem cells and plays an essential prosurvival role in pluripotent embryonic stem cells. Here we show that knockdown (KD) of Gfer in hematopoietic stem cells (HSCs) compromises their in vivo engraftment potential and triggers a hyper-proliferative response that leads to their exhaustion. KD of Gfer in HSCs does not elicit a significant alteration of mitochondrial morphology or loss of cell viability. However, these cells possess significantly reduced levels of the cyclin-dependent kinase inhibitor p27(kip1). In contrast, overexpression of Gfer in HSCs results in significantly elevated total and nuclear p27(kip1). KD of Gfer results in enhanced binding of p27(kip1) to its inhibitor, the COP9 signalosome subunit jun activation-domain binding protein 1 (Jab1), leading to its down-regulation. Conversely, overexpression of Gfer results in its enhanced binding to Jab1 and inhibition of the Jab1-p27(kip1) interaction. Furthermore, normalization of p27(kip1) in Gfer-KD HSCs rescues their in vitro proliferation deficits. Taken together, our data demonstrate the presence of a novel Gfer-Jab1-p27(kip1) pathway in HSCs that functions to restrict abnormal proliferation. |
format | Text |
id | pubmed-3078070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-30780702011-06-30 Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells Teng, Ellen C. Todd, Lance R. Ribar, Thomas J. Lento, William Dimascio, Leah Means, Anthony R. Sankar, Uma Mol Biol Cell Articles Growth factor erv1-like (Gfer) is an evolutionarily conserved sulfhydryl oxidase that is enriched in embryonic and adult stem cells and plays an essential prosurvival role in pluripotent embryonic stem cells. Here we show that knockdown (KD) of Gfer in hematopoietic stem cells (HSCs) compromises their in vivo engraftment potential and triggers a hyper-proliferative response that leads to their exhaustion. KD of Gfer in HSCs does not elicit a significant alteration of mitochondrial morphology or loss of cell viability. However, these cells possess significantly reduced levels of the cyclin-dependent kinase inhibitor p27(kip1). In contrast, overexpression of Gfer in HSCs results in significantly elevated total and nuclear p27(kip1). KD of Gfer results in enhanced binding of p27(kip1) to its inhibitor, the COP9 signalosome subunit jun activation-domain binding protein 1 (Jab1), leading to its down-regulation. Conversely, overexpression of Gfer results in its enhanced binding to Jab1 and inhibition of the Jab1-p27(kip1) interaction. Furthermore, normalization of p27(kip1) in Gfer-KD HSCs rescues their in vitro proliferation deficits. Taken together, our data demonstrate the presence of a novel Gfer-Jab1-p27(kip1) pathway in HSCs that functions to restrict abnormal proliferation. The American Society for Cell Biology 2011-04-15 /pmc/articles/PMC3078070/ /pubmed/21346186 http://dx.doi.org/10.1091/mbc.E10-08-0723 Text en © 2011 Teng et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,“ “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Teng, Ellen C. Todd, Lance R. Ribar, Thomas J. Lento, William Dimascio, Leah Means, Anthony R. Sankar, Uma Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title | Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title_full | Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title_fullStr | Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title_full_unstemmed | Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title_short | Gfer inhibits Jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
title_sort | gfer inhibits jab1-mediated degradation of p27(kip1) to restrict proliferation of hematopoietic stem cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078070/ https://www.ncbi.nlm.nih.gov/pubmed/21346186 http://dx.doi.org/10.1091/mbc.E10-08-0723 |
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