Transactivation-deficient Delta TA-p73 inhibits p53 by direct competition for DNA binding: implications for tumorigenesis.
The p53 family member p73 displays significant structural and functional homology to p53. However, instead of mutational inactivation, overexpression of wild-type p73 has been reported in various tumor types compared with normal tissues, arguing against a classical tumor suppressor function. Recently, N-terminally truncated, transactivation-deficient p73 isoforms (DeltaTA-p73) have been identified as a second class of p73 proteins. Because overexpression of p73 in tumors includes DeltaTA-p73, we further characterized these novel p73 isoforms. We show that DeltaTA-p73 retains DNA-binding competence but lacks transactivation functions, resulting in an inability to induce growth arrest and apoptosis. Importantly, DeltaTA-p73 acts as a dominant-negative inhibitor of p53 and full-length p73 (TA-p73). We demonstrate that inhibition of p53 involves competition for DNA binding, whereas TA-p73 can be inhibited by direct protein-protein interaction. Further, we show that up-regulation of endogenous p73 just like ectopic overexpression of DeltaTA-p73 confers resistance to p53-mediated apoptosis induced by the chemotherapeutic agent H-7. Because inhibition of p53 is a common theme in human cancer, our data strongly support a role of DeltaTA-p73 expression for tumor formation.
Stiewe
Thorsten
T
Centre for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen, Medical School, D-45122 Essen, Germany.
Theseling
Carmen C
CC
Pützer
Brigitte M
BM
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D001667:Binding, Competitive; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005434:Flow Cytometry; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics*; D016678:Genome; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D008156:Luciferases