Please use this identifier to cite or link to this item: http://hdl.handle.net/10077/10119
Title: Metabolic control of YAP/TAZ by the Mevalonate Pathway
Authors: Sorrentino, Giovanni
Supervisore/Tutore: Del Sal, Giannino
Issue Date: 28-Apr-2014
Publisher: Università degli studi di Trieste
Abstract: The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate–YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
Ciclo di dottorato: XXVI Ciclo
metadata.dc.subject.classification: SCUOLA DI DOTTORATO DI RICERCA IN BIOMEDICINA MOLECOLARE
Description: 2012/2013
Keywords: Cancer
Small molecules
Hippo pathway
Metabolism
p53
Language: en
Type: Doctoral Thesis
Settore scientifico-disciplinare: BIO/13 BIOLOGIA APPLICATA
NBN: urn:nbn:it:units-12541
Appears in Collections:Scienze biologiche

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