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Dev Cell. 2017 Sep 25;42(6):667-680.e4. doi: 10.1016/j.devcel.2017.08.013.

Hippo Reprograms the Transcriptional Response to Ras Signaling.

Author information

1
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
2
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, 3000 Leuven, Belgium; Laboratory of Computational Biology, Center for Human Genetics, and VIB-KU Leuven Center for Brain & Disease Research, University of Leuven, 3000 Leuven, Belgium.
3
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, 3000 Leuven, Belgium.
4
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
5
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
6
Laboratory of Computational Biology, Center for Human Genetics, and VIB-KU Leuven Center for Brain & Disease Research, University of Leuven, 3000 Leuven, Belgium. Electronic address: stein.aerts@kuleuven.be.
7
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, 3000 Leuven, Belgium. Electronic address: georg.halder@vib.be.
8
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: fisun.hamaratoglu@unil.ch.

Abstract

Hyperactivating mutations in Ras signaling are hallmarks of carcinomas. Ras signaling mediates cell fate decisions as well as proliferation during development. It is not known what dictates whether Ras signaling drives differentiation versus proliferation. Here we show that the Hippo pathway is critical for this decision. Loss of Hippo switches Ras activation from promoting cellular differentiation to aggressive cellular proliferation. Transcriptome analysis combined with genetic tests show that this excessive proliferation depends on the synergistic induction of Ras target genes. Using ChIP-nexus, we find that Hippo signaling keeps Ras targets in check by directly regulating the expression of two key downstream transcription factors of Ras signaling: the ETS-domain transcription factor Pointed and the repressor Capicua. Our results highlight how independent signaling pathways can impinge on each other at the level of transcription factors, thereby providing a safety mechanism to keep proliferation in check under normal developmental conditions.

KEYWORDS:

Capicua; ChIP-nexus; Drosophila; Hippo; RNA-seq; Ras; cancer; development; feedback regulation; proliferation

Comment in

PMID:
28950103
DOI:
10.1016/j.devcel.2017.08.013
[Indexed for MEDLINE]
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