Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V., Beutenbergstr. 11, 07745, Jena, Germany.
EMBO J. 2024 Oct;43(20):4578-4603. doi: 10.1038/s44318-024-00188-0. Epub 2024 Aug 29.
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.
Yes 相关蛋白 (YAP) 和其同源物，PDZ 结合基序的转录共激活因子 (TAZ)，是 Hippo 通路的主要转录下游效应物。Hippo 通路活性降低导致 YAP/TAZ 的核转位，在那里它们与 TEAD 转录因子相互作用诱导靶基因表达。无限制的 YAP/TAZ 活性会在短时间内导致过度生长和肿瘤形成，这突显了对这两个转录共激活因子进行严格控制的进化需求。在这里，我们报告 AP-1 成分 JUN 作为 YAP/TAZ 在联合靶位点的特异性抑制剂发挥作用，从而降低 YAP/TAZ 的活性。JUN 的这种功能与其异二聚体 AP-1 伙伴 FOS 和典型的 AP-1 功能无关。由于 JUN 的表达本身被 YAP/TAZ 诱导，我们的工作确定了一个 JUN 依赖性的负反馈回路，该回路在联合基因组位点缓冲 YAP/TAZ 的活性。这种负反馈回路在肝癌中被破坏，从而释放 YAP/TAZ 的全部致癌潜力。因此，我们的研究结果证明了 YAP/TAZ 和 AP-1 相互作用的额外控制层。
