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ΔNp73α inhibits PTEN expression in thyroid cancer cells
Author(s) -
Vella Veronica,
Puppin Cinzia,
Damante Giuseppe,
Vigneri Riccardo,
Sanfilippo Mariangela,
Vigneri Paolo,
Tell Gianluca,
Frasca Francesco
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24221
Subject(s) - pten , cancer research , protein kinase b , biology , pi3k/akt/mtor pathway , downregulation and upregulation , chromatin immunoprecipitation , microbiology and biotechnology , chemistry , signal transduction , gene expression , promoter , gene , biochemistry
ΔNp73 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, ΔNp73α is upregulated, whereas PTEN expression down regulated, we investigated whether ΔNp73α may influence PTEN expression in this cell model. We found that ΔNp73α overexpression in thyroid cancer cells reduces PTEN expression, whereas ΔNp73α down‐regulation by siRNA increases PTEN expression. Real‐time PCR indicated that overexpression of ΔNp73α is able to reduce PTEN mRNA levels. Moreover, chromatin immunoprecipitation (ChIP) and luciferase assays indicated that ΔNp73α 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 (TAp73α and TAp73β) bound to this DNA sequence and, at variance with ΔNp73α, stimulated PTEN promoter activity to an extent similar to that of p53. In accordance with its effect on PTEN protein levels, ΔNp73α increased phospho‐Akt protein content and, as a consequence, Mdm2‐mediated p53 degradation. This effect of ΔNp73α 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, ΔNp73α exerts its protumorigenic effect. © 2008 Wiley‐Liss, Inc.