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Cell DOI:10.1016/j.cell.2012.11.026

β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.

Publication TypeJournal Article
Year of Publication2012
AuthorsRosenbluh, J, Nijhawan, D, Cox, AG, Li, X, Neal, JT, Schafer, EJ, Zack, TI, Wang, X, Tsherniak, A, Schinzel, AC, Shao, DD, Schumacher, SE, Weir, BA, Vazquez, F, Cowley, GS, Root, DE, Mesirov, JP, Beroukhim, R, Kuo, CJ, Goessling, W, Hahn, WC
JournalCell
Volume151
Issue7
Pages1457-73
Date Published2012 Dec 21
ISSN1097-4172
KeywordsAdaptor Proteins, Signal Transducing, Animals, bcl-X Protein, beta Catenin, Cell Line, Tumor, Cell Transformation, Neoplastic, Colon, Colonic Neoplasms, Humans, Inhibitor of Apoptosis Proteins, Mice, Mice, Nude, Phosphoproteins, Proto-Oncogene Proteins c-yes, src-Family Kinases, T-Box Domain Proteins, Transcription, Genetic, Zebrafish
Abstract

Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(12)01411-0
DOI10.1016/j.cell.2012.11.026
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23245941?dopt=Abstract

Alternate JournalCell
PubMed ID23245941
PubMed Central IDPMC3530160
Grant ListR01 GM074024 / GM / NIGMS NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
R01 DK085720 / DK / NIDDK NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U01 DK085527 / DK / NIDDK NIH HHS / United States
F32 CA124082 / CA / NCI NIH HHS / United States
R01 CA109467 / CA / NCI NIH HHS / United States
R01 CA140545 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
F32 GM090437 / GM / NIGMS NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
R01 DK090311 / DK / NIDDK NIH HHS / United States
U01 CA151920 / CA / NCI NIH HHS / United States