Journal
NATURE CELL BIOLOGY
Volume 17, Issue 9, Pages 1218-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3216
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Funding
- Italian Association for Cancer Research (AIRC)
- AIRC-MFAG
- AIRC Special Program Molecular Clinical Oncology '5 per mille'
- Epigenetics Flagship project CNR-MIUR grants
- AIRC-IG Grant
- ERC-ADG
- FIRB Accordi di Programma [RBAP11T3WB]
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YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.
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