The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.

The p53 tumor suppressor gene is the most frequent target for genetic alterations in human cancers, whereas the recently discovered homologues p73 and p63 are rarely mutated. We and others have previously reported that human tumor-derived p53 mutants can engage in a physical association with different isoforms of p73, inhibiting their transcriptional activity. Here, we report that human tumor-derived p53 mutants can associate in vitro and in vivo with p63 through their respective core domains. We show that the interaction with mutant p53 impairs in vitro and in vivo sequence-specific DNA binding of p63 and consequently affects its transcriptional activity. We also report that in cells carrying endogenous mutant p53, such as T47D cells, p63 is unable to recruit some of its target gene promoters. Unlike wild-type p53, the binding to specific p53 mutants markedly counteracts p63-induced growth inhibition. This effect is, at least partially, mediated by the core domain of mutant p53. Thus, inactivation of p53 family members may contribute to the biological properties of specific p53 mutants in promoting tumorigenesis and in conferring selective survival advantage to cancer cells.

In our recent article, there was an omission in the Acknowledgments section. The corrected text appears here.

No abstract

Many in vitro and in vivo evidence have shown that the status of p53 is a key determinant in the response of tumor cells to anticancer treatment. Here we provide evidence that peptide-mediated targeting of the protein complex mutantp53/p73 enhances the response of mutant p53 tumor cells to commonly used anticancer drugs. Indeed, we show that the disruption of the protein complex mutantp53/p73 and the consequent restoration of p73 transcriptional effects, through the activity of short interfering peptides, render mutant p53 cells more prone to the killing of adriamycin and cisplatin. Of note, the activity of the short interfering peptides is mutant p53 specific and causes no effects on wt-p53 and p53 null cells. Our findings highlight the protein complex mutantp53/ p73 as a molecular target, whose successful overriding through the selective activity of small interfering peptides, might contribute to the optimization of mutant p53 tumor treatments.