Document Detail


DeltaNp73alpha inhibits PTEN expression in thyroid cancer cells.
MedLine Citation:
PMID:  19173293     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DeltaNp73 is a N-terminally truncated p53 family member with a dominant negative function, which is upregulated in cancer. PTEN is a lipid phosphatase, which is involved in the attenuation of tyrosine kinase signaling. PTEN expression is increased by p53, and its function is blunted in several malignancies. Because in most of the thyroid carcinomas, DeltaNp73alpha is upregulated, whereas PTEN expression down regulated, we investigated whether DeltaNp73alpha may influence PTEN expression in this cell model. We found that DeltaNp73alpha overexpression in thyroid cancer cells reduces PTEN expression, whereas DeltaNp73alpha down-regulation by siRNA increases PTEN expression. Real-time PCR indicated that overexpression of DeltaNp73alpha is able to reduce PTEN mRNA levels. Moreover, chromatin immunoprecipitation (ChIP) and luciferase assays indicated that DeltaNp73alpha binds to -1031-779 region of the PTEN promoter, which is a different site than that for p53, thereby inhibiting promoter activity. Interestingly, also the transcriptionally active p73 isoforms (TAp73alpha and TAp73beta) bound to this DNA sequence and, at variance with DeltaNp73alpha, stimulated PTEN promoter activity to an extent similar to that of p53. In accordance with its effect on PTEN protein levels, DeltaNp73alpha increased phospho-Akt protein content and, as a consequence, Mdm2-mediated p53 degradation. This effect of DeltaNp73alpha resulted in increased thyroid cancer cell proliferation and reduced apoptosis and was reverted by the PI3-kinase inhibitor LY294002, indicating the role of Akt pathway in this effect. Taken together, these results indicate a novel p73 regulated mechanism for PTEN expression in thyroid cancer cells, and that, also through this mechanism, DeltaNp73alpha exerts its protumorigenic effect.
Authors:
Veronica Vella; Cinzia Puppin; Giuseppe Damante; Riccardo Vigneri; Mariangela Sanfilippo; Paolo Vigneri; Gianluca Tell; Francesco Frasca
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  124     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-04-01     Completed Date:  2009-04-14     Revised Date:  2009-06-03    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2539-48     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Cell Survival
DNA-Binding Proteins / physiology*
Down-Regulation
Humans
Mice
NIH 3T3 Cells
Nuclear Proteins / physiology*
PTEN Phosphohydrolase / antagonists & inhibitors,  genetics*
Promoter Regions, Genetic*
Thyroid Neoplasms / genetics*,  pathology
Tumor Suppressor Protein p53 / analysis
Tumor Suppressor Proteins / physiology*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

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


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