p73alpha expression induces both accumulation and activation of wt-p53 independent of the p73alpha transcriptional activity.
The p53 tumor suppressor gene belongs to a multigene family that includes two paralogues, p63 and p73. p73alpha has common activities with p53, such as DNA binding and transactivation, and can thus activate the transcription of p53-responsive genes. Using the adenoviral system, we report that an overexpression of either wt-p73alpha or one of the two transcriptional inactive mutants, deltaNp73alpha or p73alphaR292H, induces an accumulation of the endogenous wt-p53 expressed in the three transformed cell lines, SK-N-SH, MCF-7 and U-2OS, without stimulating the p53 gene transcription. p73-mediated accumulation of p53 protein coincides with an increase of p53-target gene expression in cells expressing either wt-p73alpha or the transcriptional inactive mutant p73alphaR292H, but not deltaNp73alpha that encodes a dominant-negative mutant of both p73 and p53. The fact that an ectopic expression of p73alphaR292H leads to both accumulation of p53 and stimulation of p53 target gene expression strongly suggests that p73alpha is able to induce activation of p53. This was confirmed by showing that p73alphaR292H no longer stimulated Waf1/p21 expression in MCF7/R-A1 cells that expressed a transcriptional inactive mutant of p53. We thus conclude that p73alpha protein was able to both stabilize and activate wt-p53 protein, independent of the p73alpha transcriptional activity.
Miro-Mur
Francesc
F
Commissariat à l'énergie atomique (CEA), CNRS, Laboratoire de Cancérogenèse Moléculaire, UMR217, DRR, DSV, route du Panorama, 92265 Fontenay-aux-Roses, France.
Meiller
Anne
A
Haddada
Hedi
H
May
Evelyne
E
D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; 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