期刊
JOURNAL OF BIOCHEMISTRY
卷 150, 期 2, 页码 199-208出版社
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvr063
关键词
gene transcription; green fluorescent protein; signal transduction; tumour suppressor
资金
- Ministry of Education, Sports, Science and Technology [17081008]
- Japan Society for the Promotion of Science (JSPS) [22790275, 22590267]
- Japanese Government (Monbukagakusho) (MEXT)
- TAKASE foundation
- Grants-in-Aid for Scientific Research [17081008, 22790275, 23790325] Funding Source: KAKEN
The mammalian Hippo pathway is composed of mammalian Ste20-like (MST) kinases and large tumour suppressor (LATS) kinases. Upon the activation of the pathway, MST kinases phosphorylate and activate LATS kinases, which in turn phosphorylate transcriptional co-activators, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), recruit them to the cytosol from the nucleus and turn off cell cycle-promoting and anti-apoptotic gene transcriptions. Thus, the pathway restricts cell overgrowth and prevents tumourigenesis. Although a high cell density and stress signallings are known to activate the pathway, no specific stimulators are so far reported. As the dysfunction of the pathway is frequent in human cancers and correlates with poor prognosis, it is important to find out reagents that stimulate the pathway for not only basic research but also clinical medicine. We here developed a cell-based method of screening reagents that induce the recruitment of YAP to the cytosol. Using this method, we found that dobutamine inhibits the YAP-dependent gene transcription. Contrary to our expectations, the effect of dobutamine is independent of the Hippo pathway but our method opens the possibility to discover Hippo pathway stimulators or Hippo-independent YAP inhibitors.
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