A Non-canonical Repressor Function of JUN Restrains YAP Activity and Liver Cancer Growth

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Aug 29

PMID 39210147

Authors

Yuliya Kurlishchuk

Anita Cindric Vranesic

Marco Jessen

Alexandra Kipping

Christin Ritter

KyungMok Kim

Paul Cramer

Bjorn von Eyss

Affiliations

Soon will be listed here.

Abstract

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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