Document Detail


Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas.
MedLine Citation:
PMID:  20889565     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n=98; P<0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).
Authors:
Nicola Amodio; Marianna Scrima; Lucia Palaia; Ali Naeem Salman; Alfina Quintiero; Renato Franco; Gerardo Botti; Pino Pirozzi; Gaetano Rocco; Nicla De Rosa; Giuseppe Viglietto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-01
Journal Detail:
Title:  The American journal of pathology     Volume:  177     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-04     Completed Date:  2011-03-21     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2622-34     Citation Subset:  AIM; IM    
Affiliation:
Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Carcinoma, Non-Small-Cell Lung / genetics,  metabolism*,  pathology
Cell Line, Tumor
Cell Proliferation
Endosomal Sorting Complexes Required for Transport / genetics,  metabolism*
Epigenomics
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / genetics,  metabolism*,  pathology
Male
Microarray Analysis
Middle Aged
PTEN Phosphohydrolase / genetics,  metabolism*
Ubiquitin-Protein Ligases / genetics,  metabolism*
Ubiquitination
Chemical
Reg. No./Substance:
0/Endosomal Sorting Complexes Required for Transport; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; EC 6.3.2.19/Nedd4 ubiquitin protein ligases; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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