Yes-associated protein (YAP) is a key downstream effector of the highly conserved Hippo signaling pathway, which regulates organ size, regeneration and tumorigenesis. Known classically to function as a transcriptional co-activator, YAP interacts with TEA domain transcription factors (TEAD1-4) to induce expression of target genes. However, a number of genes are repressed upon YAP activation, suggesting a transcriptional repressor role of YAP. Here, we report that TP73 is a direct target gene of YAP, and its transcription is repressed by YAP in a TEAD-independent manner. On the other hand, WW domains of YAP are indispensable for the regulation of TP73 expression, which may recruit YAP to TP73 gene though interaction with ZEB1 and/or RUNX2, two transcriptional repressors. Moreover, YAP-mediated repression of TP73 promotes cancer cell survival in the presence of chemotherapeutic agents, suggesting YAP-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies.

Yes-associated protein（YAP）是高度保守的Hippo信号通路的关键下游效应子，它调节器官的大小，再生和肿瘤发生。众所周知，YAP具有转录共激活因子的功能，它与TEA域转录因子（TEAD1-4）相互作用以诱导靶基因的表达。但是，许多基因在YAP激活后被阻遏，提示了YAP在转录抑制因子中的作用。在这里，我们报道TP73是YAP的直接靶基因，并且其转录受YAP以TEAD独立的方式抑制。另一方面，YAP的WW结构域对于调节TP73表达必不可少，这可能会使YAP募集到TP73基因通过与两个转录阻遏物ZEB1和/或RUNX2相互作用而产生。此外，在化学治疗剂的存在下，YAP介导的TP73的阻遏促进癌细胞的存活，这表明YAP-TP73信号传导是癌细胞对化学疗法耐药的机制。