Effects of p51/p63 missense mutations on transcriptional activities of p53downstream gene promoters

The p51/p63 gene is a homologue of p53, the product of which acts as a tran scriptional activator by binding to p53-responsive elements in the promoter regions of several p53 downstream genes. Recently, we identified four dist inct mutations in the p51/p63 gene after screening >200 human tumors and ce ll lines. Because all of the detected p51/p63 mutations were missense mutat ions, the pathogenic effect of these mutations is difficult to determine wi thout performing a functional analysis. In this study, we examined the tran scriptional activity of tumor-derived p51/p63 missense mutations using a ye ast-based assay and compared the data. with that of artificial p51/p63 miss ense mutations at residues corresponding to the positions and substituted r esidues of p53 mutation "hotspots." Although most of the p51/p63 missense m utations at the p53 hotspot residues were unable to transactivate the promo ters used in this study, the tumor-derived p51/p63 missense mutations retai ned their ability to transactivate the MDM2 and/or the BAX promoter but not the p21/WAF1 promoter. These results suggest that the p51/p63 mutation mig ht be involved in an unknown tumor suppression pathway distinct from that o f p53.