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.

Aberrant activation of β‐catenin contributes to the onset of a variety of tumors. We report that a tumor‐derived β‐catenin mutant induces accumulation and activation of the p53 tumor suppressor protein. Induction is mediated through ARF, an alternative reading frame product of the INK4A tumor suppressor locus, in a manner partially dependent on the transcription factor E2F1. In wild‐type mouse embryo fibroblasts, mutant β‐catenin inhibits cell proliferation and imposes a senescence‐like phenotype. This does not occur in cells lacking either ARF or p53, where deregulated β‐catenin actually overrides density‐dependent growth inhibition and cooperates with activated Ras in transformation. Thus, the oncogenic activity of deregulated β‐catenin is curtailed by concurrent activation of the p53 pathway, thereby providing a protective mechanism against cancer. When the p53 pathway is impaired, deregulated β‐catenin is free to manifest its oncogenic features. This can occur not only by p53 mutations, but also by ablation of ARF expression, as observed frequently in early stages of colorectal carcinogenesis.

beta-catenin is a multifunctional protein, acting both as a structural component of the cell adhesion machinery and as a transducer of extracellular signals. Deregulated beta-catenin protein expression, due to mutations in the beta-catenin gene itself or in its upstream regulator, the adenomatous polyposis coli (APC) gene, is prevalent in colorectal cancer and in several other tumor types, and attests to the potential oncogenic activity of this protein. Increased expression of beta-catenin is an early event in colorectal carcinogenesis, and is usually followed by a later mutational inactivation of the p53 tumor suppressor. To examine whether these two key steps in carcinogenesis are interrelated, we studied the effect of excess beta-catenin on p53. We report here that overexpression of beta-catenin results in accumulation of p53, apparently through interference with its proteolytic degradation. This effect involves both Mdm2-dependent and -independent p53 degradation pathways, and is accompanied by augmented transcriptional activity of p53 in the affected cells. Increased p53 activity may provide a safeguard against oncogenic deregulation of beta-catenin, and thus impose a pressure for mutational inactivation of p53 during the later stages of tumor progression.

Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor KB (NFKB) transcriptional activity in response to the cytokine tumor necrosis factor A (TNFA). Conversely, down-regulation of endogenous mutant p53 sensitizes cancer cells to the apoptotic effects of TNFA. Analysis of human head and neck tumors and lung tumors reveals a close correlation between the presence of abundant mutant p53 proteins and the constitutive activation of NFKB. Together, these findings suggest that p53 mutations may promote cancer progression by augmenting NFKB activation in the context of chronic inflammation. [Cancer Res 2007;67(6):2396-401]