The Transcriptional Coactivator Yes-Associated Protein Drives p73 Gene-Target Specificity in Response to DNA Damage

Abstract

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.

MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma

“…YAP1 is a well-documented proapoptotic transcriptional factor, and inhibition of its expression greatly reduces cisplatin-induced apoptosis. 40,41 Given that the results of our present study showed that miR-141 targets YAP1 and negatively regulates the expression of YAP1, it is likely that miR-141 exerts its anti-apoptotic effect, at least in part, through repressing YAP1 expression.…”

“…Among the predicted 429 candidate genes, we studied the functional role of human Yes-Associated Protein (YAP1) (NM_006106) further, because it has been reported to be a cisplatin-induced apoptosis-related gene. 40 First, we investigated the effects of transfection of the miR-141 precursor on YAP1 expression in cisplatinsensitive KYSE cell lines. The quantitative reverse transcription-PCR and western blotting analyses revealed that expression levels of YAP1 messenger RNA and protein were decreased in miR-141 precursor-transfected cells as compared with control precursortransfected cells (Figure 5a), which indicated that the expression of YAP1 was inhibited by miR-141.…”

Some p53-binding proteins that can function as arbiters of life and death

“…The polyproline region of p73 that is recognized by Pin1 does in fact overlap with the binding site for YAP, an essential factor directing p73 towards proapoptotic promoters. 74 Intriguingly, conformational alteration of this domain would be expected to interfere with binding of the ubiquitin ligase Itch, 75 thus providing a mechanistic explanation for the observed role of Pin1 in p73 stabilization. 68 Given the similar effects exerted on p53 and p73, Pin1 may well represent a common mediator for cooperative activity among the p53 family members.…”

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

“…Additionally, YAP has been reported as a potential integrator of cell death processes and autophagy during cellular stress [30–32]. When YAP is phosphorylated at serine 127, it remains in the cytoplasm and is unable to interact with p73, resulting in impaired transcription of the Nlrc4 gene [25,33]. Salmonella induces YAP phosphorylation during B cell infection, triggering the transcriptional downregulation of the Nlrc4 gene [25].…”