Document Detail


Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2.
MedLine Citation:
PMID:  21036916     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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:
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:
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:
Created Date:  2010-12-20     Completed Date:  2011-01-28     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L64-72     Citation Subset:  IM    
Affiliation:
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Division / 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:
R01 CA100907/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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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