Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1.

中文翻译：

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JUN 的非经典抑制功能抑制 YAP 活性和肝癌生长。


Yes 相关蛋白 （YAP） 及其同源物，即具有 PDZ 结合基序 （TAZ） 的转录共激活因子，是 Hippo 通路的主要转录下游效应子。Hippo 通路活性降低导致 YAP/TAZ 核易位，在那里它们与 TEAD 转录因子相互作用以诱导靶基因表达。不受限制的 YAP/TAZ 活性可在短时间内导致过度生长和肿瘤形成，这强调了严格控制这两种转录共激活因子的进化需求。在这里，我们报道了 AP-1 组分 JUN 在联合靶位点充当 YAP/TAZ 的特异性抑制因子，以降低 YAP/TAZ 活性。JUN 的这种功能独立于其异二聚体 AP-1 伴侣 FOS 和经典 AP-1 功能。由于 JUN 的表达本身是由 YAP/TAZ 诱导的，因此我们的工作确定了一个 JUN 依赖性负反馈回路，该回路可缓冲关节基因组位点的 YAP/TAZ 活性。这种负反馈回路在肝癌中被破坏，以释放 YAP/TAZ 的全部致癌潜力。因此，我们的结果证明了 YAP/TAZ 和 AP-1 相互作用的额外控制层。