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 fi rst identified p53 relative, p73, was reported to be monoallelically expres sed in normal tissues, In some tumors, loss of heterozygosity was associate d with overexpression of the silent allele, Human p73 alpha was transfected into the wild-type p53-expressing human ovarian carcinoma cell line A2780, Unlike human osteosarcoma Saos-2 cells, A2780 cells could tolerate hyperex pression of p73 alpha and clones overexpressing p73 alpha could be isolated . No p53-p73 protein-protein interaction was found in these clones in co-im munoprecipitation experiments. Endogenous p53 transcriptional activity was markedly decreased both when p73 was integrated into the genome and in tran sient transfections using a reporter plasmid containing the p53 binding sit e linked to luciferase. Transient transfection of p73 with a mutation in th e DNA-binding domain did not show these effects, The competition for p53 DN A binding by p73 alpha was also evident in gel shift experiments, The resul ts 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 ina ctivation of p53.