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Hippo reprograms the transcriptional response to Ras signaling

Pascual, Justine, Jacobs, Jelle, Sansores-Garcia, Leticia, Natarajan, Malini, Zeitlinger, Julia, Aerts, Stein, Halder, Georg and Hamaratoglu Dion, Fisun 2017. Hippo reprograms the transcriptional response to Ras signaling. Developmental Cell 42 (6) , 667-680.e4. 10.1016/j.devcel.2017.08.013

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier Cell press
ISSN: 1534-5807
Date of First Compliant Deposit: 2 January 2019
Date of Acceptance: 17 August 2017
Last Modified: 18 Oct 2019 23:12
URI: http://orca.cf.ac.uk/id/eprint/118010

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