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The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells
Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G(0)/G(1) switch gene 2 (G0S2) are enriched in lineage(−) Sca...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365016/ https://www.ncbi.nlm.nih.gov/pubmed/22693613 http://dx.doi.org/10.1371/journal.pone.0038280 |
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author | Yamada, Takeshi Park, Chun Shik Burns, Audrea Nakada, Daisuke Lacorazza, H. Daniel |
author_facet | Yamada, Takeshi Park, Chun Shik Burns, Audrea Nakada, Daisuke Lacorazza, H. Daniel |
author_sort | Yamada, Takeshi |
collection | PubMed |
description | Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G(0)/G(1) switch gene 2 (G0S2) are enriched in lineage(−) Sca-1(+) c-kit(+) (LSK) CD150(+) CD48(−) CD41(−) cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150(+) CD48(−) cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150(+) CD48(−)) and progenitor cells (LS(−)K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150(+) CD48(−) cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus. |
format | Online Article Text |
id | pubmed-3365016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33650162012-06-12 The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells Yamada, Takeshi Park, Chun Shik Burns, Audrea Nakada, Daisuke Lacorazza, H. Daniel PLoS One Research Article Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G(0)/G(1) switch gene 2 (G0S2) are enriched in lineage(−) Sca-1(+) c-kit(+) (LSK) CD150(+) CD48(−) CD41(−) cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150(+) CD48(−) cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150(+) CD48(−)) and progenitor cells (LS(−)K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150(+) CD48(−) cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus. Public Library of Science 2012-05-31 /pmc/articles/PMC3365016/ /pubmed/22693613 http://dx.doi.org/10.1371/journal.pone.0038280 Text en Yamada et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Yamada, Takeshi Park, Chun Shik Burns, Audrea Nakada, Daisuke Lacorazza, H. Daniel The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title | The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title_full | The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title_fullStr | The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title_full_unstemmed | The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title_short | The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells |
title_sort | cytosolic protein g0s2 maintains quiescence in hematopoietic stem cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365016/ https://www.ncbi.nlm.nih.gov/pubmed/22693613 http://dx.doi.org/10.1371/journal.pone.0038280 |
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