p73 competes with p53 and attenuates its response in a human ovarian cancer cell line.
The transcriptional activity of the p53 tumor suppressor protein is crucial for the regulation of cell growth, apoptosis and tumor progression. The first identified p53 relative, p73, was reported to be monoallelically expressed in normal tissues. In some tumors, loss of heterozygosity was associated with overexpression of the silent allele. Human p73alpha was transfected into the wild-type p53-expressing human ovarian carcinoma cell line A2780. Unlike human osteosarcoma Saos-2 cells, A2780 cells could tolerate hyperexpression of p73alpha and clones over-expressing p73alpha could be isolated. No p53-p73 protein-protein interaction was found in these clones in co-immunoprecipitation experiments. Endogenous p53 transcriptional activity was markedly decreased both when p73 was integrated into the genome and in transient transfections using a reporter plasmid containing the p53 binding site linked to luciferase. Transient transfection of p73 with a mutation in the DNA-binding domain did not show these effects. The competition for p53 DNA binding by p73alpha was also evident in gel shift experiments. The results suggest that p73 can modulate p53 function by inhibiting its DNA binding and that overexpression of p73 in tumors might be a novel mechanism of inactivation of p53.
Vikhanskaya
F
F
Molecular Pharmacology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157 Milan, Italy.
D'Incalci
M
M
Broggini
M
M
D001665:Binding Sites; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D011233:Precipitin Tests; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin