Document Detail

Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis.
MedLine Citation:
PMID:  20395445     Owner:  NLM     Status:  MEDLINE    
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies. Fibroblasts isolated from IPF patients display pathological activation of PI3K/Akt caused by low PTEN phosphatase activity. This enables these cells to escape the negative proliferative properties of polymerized collagen. The mechanism underlying low PTEN activity in IPF fibroblasts is unclear, but our prior studies indicate that membrane-associated PTEN expression is decreased in these cells. Caveolin-1 is an integral membrane protein whose expression is decreased in IPF lung tissue, but how low caveolin-1 contributes to pathological fibrosis is incompletely understood. The objective of this study was to examine the hypothesis that caveolin-1 regulates PTEN function in IPF fibroblasts. Here we demonstrate that caveolin-1 expression is a determinant of membrane PTEN levels and show that PTEN interacts with caveolin-1 via its caveolin-1-binding sequence. We demonstrate that caveolin-1 expression is low in IPF fibroblasts and that this correlates with low membrane PTEN levels, whereas overexpression of caveolin-1 restores membrane PTEN levels, inhibits Akt phosphorylation, and suppresses proliferation. We demonstrate that caveolin-1 and PTEN expression are low in myofibroblasts within IPF fibroblastic foci. These data indicate that IPF fibroblasts display low caveolin-1 expression, which results in low membrane-associated PTEN expression. This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation.
Hong Xia; Wajahat Khalil; Judy Kahm; Jose Jessurun; Jill Kleidon; Craig A Henke
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-04-15
Journal Detail:
Title:  The American journal of pathology     Volume:  176     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-03     Completed Date:  2010-10-04     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2626-37     Citation Subset:  AIM; IM    
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MeSH Terms
Apoptosis / physiology
Caveolin 1 / genetics,  metabolism*
Cell Line
Cell Membrane / metabolism
Collagen / metabolism
Fibroblasts / cytology,  metabolism
Idiopathic Pulmonary Fibrosis / metabolism*
PTEN Phosphohydrolase / genetics,  metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Grant Support
P01 HL091775/HL/NHLBI NIH HHS; P01 HL091775-026586/HL/NHLBI NIH HHS; P01 HL91775/HL/NHLBI NIH HHS; R01 HL074882/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Caveolin 1; 9007-34-5/Collagen; EC Proteins c-akt; EC protein, human; EC Phosphohydrolase

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