JUN的非典型抑制功能可抑制YAP的活性和肝癌的生长。

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-08-29 DOI:10.1038/s44318-024-00188-0
Yuliya Kurlishchuk, Anita Cindric Vranesic, Marco Jessen, Alexandra Kipping, Christin Ritter, KyungMok Kim, Paul Cramer, Björn von Eyss
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引用次数: 0

摘要

是相关蛋白(YAP)及其同源物--具有 PDZ 结合基调的转录辅激活因子(TAZ)是 Hippo 通路的主要转录下游效应因子。Hippo 通路活性的降低会导致 YAP/TAZ 的核转位,它们在核转位中与 TEAD 转录因子相互作用,诱导目标基因的表达。不受约束的 YAP/TAZ 活性可在短时间内导致过度生长和肿瘤形成,这突出表明了对这两种转录辅激活因子进行严格控制的进化需要。在这里,我们报告了 AP-1 成分 JUN 在联合靶位点作为 YAP/TAZ 的特异性抑制因子来降低 YAP/TAZ 的活性。JUN 的这种功能与其异源 AP-1 伙伴 FOS 和典型 AP-1 功能无关。由于 JUN 的表达本身就受到 YAP/TAZ 的诱导,我们的研究发现了一个依赖 JUN 的负反馈环,它可以缓冲 YAP/TAZ 在联合基因组位点的活性。这一负反馈环在肝癌中被破坏,从而释放出 YAP/TAZ 的全部致癌潜能。因此,我们的研究结果表明,YAP/TAZ 和 AP-1 的相互作用又多了一层控制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth.

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.

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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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