Delta Np73 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, Delta Np73 alpha is upregulated, whereas PTEN expression down regulated, we investigated whether Delta Np73 alpha may influence PTEN expression in this cell model. We found that Delta Np73 alpha overexpression in thyroid cancer cells reduces PTEN expression, whereas Delta Np73 alpha down-regulation by siRNA increases PTEN expression. Real-time PCR indicated that overexpression of Delta Np73 alpha is able to reduce PTEN mRNA levels. Moreover, chromatin immunoprecipitation (ChIP) and luciferase assays indicated that Delta Np73 alpha 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 (TAp73 alpha and TAp73 beta) bound to this DNA sequence and, at variance with Delta Np73 alpha, stimulated PTEN promoter activity to an extent similar to that of p53. In accordance with its effect on PTEN protein levels, Delta Np73 alpha increased phospho-Akt protein content and, as a consequence, Mdm2-mediated p53 degradation. This effect of Delta Np73 alpha 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, Delta Np73 alpha exerts its protumorigenic effect

DeltaNp73alpha inhibits PTEN expression in thyroid cancer cells

VIGNERI, PAOLO;FRASCA, FRANCESCO;VELLA, VERONICA
2009-01-01

Abstract

Delta Np73 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, Delta Np73 alpha is upregulated, whereas PTEN expression down regulated, we investigated whether Delta Np73 alpha may influence PTEN expression in this cell model. We found that Delta Np73 alpha overexpression in thyroid cancer cells reduces PTEN expression, whereas Delta Np73 alpha down-regulation by siRNA increases PTEN expression. Real-time PCR indicated that overexpression of Delta Np73 alpha is able to reduce PTEN mRNA levels. Moreover, chromatin immunoprecipitation (ChIP) and luciferase assays indicated that Delta Np73 alpha 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 (TAp73 alpha and TAp73 beta) bound to this DNA sequence and, at variance with Delta Np73 alpha, stimulated PTEN promoter activity to an extent similar to that of p53. In accordance with its effect on PTEN protein levels, Delta Np73 alpha increased phospho-Akt protein content and, as a consequence, Mdm2-mediated p53 degradation. This effect of Delta Np73 alpha 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, Delta Np73 alpha exerts its protumorigenic effect
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/7253
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