Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2. | |
MedLine Citation:
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PMID: 21036916 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, resulting from proliferation of smooth-muscle-like cells, which have mutations in the tumor suppressor genes TSC1 or TSC2. Among 277 LAM patients, severe disease was associated with hypoxia and elevated red blood cell indexes that accompanied reduced pulmonary function. Because high red cell indexes could result from hypoxemia-induced erythropoietin (EPO) production, and EPO is a smooth muscle cell mitogen, we investigated effects of EPO in human cells with genetic loss of tuberin function, and we found that EPO increased proliferation of human TSC2-/-, but not of TSC2+/-, cells. A discrete population of cells grown from explanted lungs was characterized by the presence of EPO receptor and loss of heterozygosity for TSC2, consistent with EPO involvement. In LAM cells from lung nodules, EPO was localized to the extracellular matrix, supporting evidence for activation of an EPO-driven signaling pathway. Although the high red cell mass of LAM patients could be related to advanced disease, we propose that EPO, synthesized in response to episodic hypoxia, may increase disease progression by enhancing the proliferation of LAM cells. |
Authors:
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Yoshihiko Ikeda; Angelo M Taveira-DaSilva; Gustavo Pacheco-Rodriguez; Wendy K Steagall; Souheil El-Chemaly; Bernadette R Gochuico; Rose M May; Olanda M Hathaway; Shaowei Li; Ji-an Wang; Thomas N Darling; Mario Stylianou; Joel Moss |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2010-10-29 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 300 ISSN: 1522-1504 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-20 Completed Date: 2011-01-28 Revised Date: 2013-07-03 |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L64-72 Citation Subset: IM |
Affiliation:
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National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA. |
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MeSH Terms | |
Descriptor/Qualifier:
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Cell Division
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drug effects,
physiology* Disease Progression Erythropoietin / pharmacology*, physiology* Genes, Tumor Suppressor* Humans Lung Neoplasms / genetics*, metabolism, pathology Lymphangioleiomyomatosis / genetics, metabolism, pathology Mutation* Signal Transduction / genetics Tumor Suppressor Proteins / deficiency, drug effects, genetics* |
Grant Support | |
ID/Acronym/Agency:
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R01 CA100907/CA/NCI NIH HHS |
Chemical | |
Reg. No./Substance:
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0/Tumor Suppressor Proteins; 0/tuberous sclerosis complex 1 protein; 11096-26-7/Erythropoietin; 4JG2LF96VF/tuberous sclerosis complex 2 protein |
Comments/Corrections |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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