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Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease
In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced plu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110013/ https://www.ncbi.nlm.nih.gov/pubmed/27821551 http://dx.doi.org/10.1084/jem.20151920 |
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author | Azad, Priti Zhao, Huiwen W. Cabrales, Pedro J. Ronen, Roy Zhou, Dan Poulsen, Orit Appenzeller, Otto Hsiao, Yu Hsin Bafna, Vineet Haddad, Gabriel G. |
author_facet | Azad, Priti Zhao, Huiwen W. Cabrales, Pedro J. Ronen, Roy Zhou, Dan Poulsen, Orit Appenzeller, Otto Hsiao, Yu Hsin Bafna, Vineet Haddad, Gabriel G. |
author_sort | Azad, Priti |
collection | PubMed |
description | In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology. |
format | Online Article Text |
id | pubmed-5110013 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51100132017-05-14 Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease Azad, Priti Zhao, Huiwen W. Cabrales, Pedro J. Ronen, Roy Zhou, Dan Poulsen, Orit Appenzeller, Otto Hsiao, Yu Hsin Bafna, Vineet Haddad, Gabriel G. J Exp Med Research Articles In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology. The Rockefeller University Press 2016-11-14 /pmc/articles/PMC5110013/ /pubmed/27821551 http://dx.doi.org/10.1084/jem.20151920 Text en © 2016 Azad 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.rupress.org/terms). 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 | Research Articles Azad, Priti Zhao, Huiwen W. Cabrales, Pedro J. Ronen, Roy Zhou, Dan Poulsen, Orit Appenzeller, Otto Hsiao, Yu Hsin Bafna, Vineet Haddad, Gabriel G. Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title | Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title_full | Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title_fullStr | Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title_full_unstemmed | Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title_short | Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease |
title_sort | senp1 drives hypoxia-induced polycythemia via gata1 and bcl-xl in subjects with monge’s disease |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110013/ https://www.ncbi.nlm.nih.gov/pubmed/27821551 http://dx.doi.org/10.1084/jem.20151920 |
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