ΔNp73α inhibits PTEN expression in thyroid cancer cells
Veronica Vella
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
The first two authors contributed equally to this work.
Search for more papers by this authorCinzia Puppin
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
The first two authors contributed equally to this work.
Search for more papers by this authorGiuseppe Damante
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
Search for more papers by this authorCorresponding Author
Riccardo Vigneri
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Fax: +39-095-472988
Endocrinologia–Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, PO Garibaldi Nesima, Via Palermo 636, 95122 Catania, ItalySearch for more papers by this authorMariangela Sanfilippo
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Search for more papers by this authorPaolo Vigneri
Department of Biomedical Sciences, Section of General Pathology, University of Catania, Catania, Italy
Search for more papers by this authorGianluca Tell
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
Search for more papers by this authorFrancesco Frasca
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Search for more papers by this authorVeronica Vella
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
The first two authors contributed equally to this work.
Search for more papers by this authorCinzia Puppin
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
The first two authors contributed equally to this work.
Search for more papers by this authorGiuseppe Damante
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
Search for more papers by this authorCorresponding Author
Riccardo Vigneri
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Fax: +39-095-472988
Endocrinologia–Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, PO Garibaldi Nesima, Via Palermo 636, 95122 Catania, ItalySearch for more papers by this authorMariangela Sanfilippo
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Search for more papers by this authorPaolo Vigneri
Department of Biomedical Sciences, Section of General Pathology, University of Catania, Catania, Italy
Search for more papers by this authorGianluca Tell
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy
Search for more papers by this authorFrancesco Frasca
Department of Internal Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Search for more papers by this authorAbstract
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.
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