Show simple item record

dc.contributor.authorBarry, Evan R.en_US
dc.contributor.authorMorikawa, Teppeien_US
dc.contributor.authorButler, Brian L.en_US
dc.contributor.authorShrestha, Kritien_US
dc.contributor.authorde la Rosa, Rosemarieen_US
dc.contributor.authorYan, Kelley S.en_US
dc.contributor.authorFuchs, Charles S.en_US
dc.contributor.authorMagness, Scott T.en_US
dc.contributor.authorSmits, Ronen_US
dc.contributor.authorOgino, Shujien_US
dc.contributor.authorKuo, Calvin J.en_US
dc.contributor.authorCamargo, Fernando D.en_US
dc.date.accessioned2014-02-18T18:11:09Z
dc.date.issued2012en_US
dc.identifier.citationBarry, E. R., T. Morikawa, B. L. Butler, K. Shrestha, R. de la Rosa, K. S. Yan, C. S. Fuchs, et al. 2012. “Restriction of intestinal stem cell expansion and the regenerative response by YAP.” Nature 493 (7430): 106-110. doi:10.1038/nature11693. http://dx.doi.org/10.1038/nature11693.en
dc.identifier.issn0028-0836en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11717550
dc.description.abstractA remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signaling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. The mechanisms that counterbalance Wnt-driven proliferation are poorly understood. We demonstrate here that YAP, a protein known for its powerful growth-inducing and oncogenic properties1-2, has an unexpected growth-suppressive function restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells (ISCs) and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signaling independently of the APC/Axin/GSK3β complex partly by limiting the activity of Dishevelled (DVL). DVL signals in the nucleus of ISCs and its forced expression leads to enhanced Wnt signaling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas (CRC) and its expression can restrict the growth of CRC xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nature11693en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536889/pdf/en
dash.licenseLAAen_US
dc.titleRestriction of intestinal stem cell expansion and the regenerative response by YAPen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNatureen
dash.depositing.authorFuchs, Charles S.en_US
dc.date.available2014-02-18T18:11:09Z
dc.identifier.doi10.1038/nature11693*
dash.authorsorderedfalse
dash.contributor.affiliatedCamargo, Fernando
dash.contributor.affiliatedOgino, Shuji
dash.contributor.affiliatedFuchs, Charles


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record