期刊
NATURE CELL BIOLOGY
卷 16, 期 4, 页码 357-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2936
关键词
-
类别
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- AIRC Special Program Molecular Clinical Oncology
- Italian Ministry of Education, University and Research (COFIN, FIRB-accordi di programma 2010) [RBAP10XKNC_003]
- Italian Ministry of Education, University and Research [FIRB RBAP11Z4Z9, RBFR10V8K6]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据