RRC ID 28442
Author Ota M, Sasaki H.
Title Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling.
Journal Development
Abstract Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its co-activator protein Yki. Here, we show that mouse Tead proteins regulate cell proliferation by mediating Hippo signaling. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of endogenous Tead proteins by modulating nuclear localization of a Yki homolog, Yap1, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap1 overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition and promotion of tumor formation. Growth-promoting activities of various Yap1 mutants correlated with their Tead-co-activator activities. Tead2-VP16 and Yap1 regulated largely overlapping sets of genes. However, only a few of the Tead/Yap1-regulated genes in NIH3T3 cells were affected in Tead1(-/-);Tead2(-/-) or Yap1(-/-) embryos. Most of the previously identified Yap1-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap1 and Tead1 varied depending on cell type. Strong nuclear accumulation of Yap1 and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap1 regulate cell proliferation differ depending on the cell type, and Tead, Yap1 and Hippo signaling may play multiple roles in mouse embryos.
Volume 135(24)
Pages 4059-69
Published 2008-12
DOI 10.1242/dev.027151
PII dev.027151
PMID 19004856
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism Animals Base Sequence Cell Count Cell Line Cell Proliferation* Cell Transformation, Neoplastic Contact Inhibition / genetics Contact Inhibition / physiology* DNA Primers / genetics DNA-Binding Proteins / deficiency DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Embryonic Development / genetics Embryonic Development / physiology Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism* Mice Mice, Knockout Mice, Mutant Strains Mice, Transgenic NIH 3T3 Cells Phosphoproteins / genetics Phosphoproteins / metabolism Signal Transduction Transcription Factors / deficiency Transcription Factors / genetics Transcription Factors / metabolism* Transcriptional Activation
IF 5.413
Times Cited 168
WOS Category DEVELOPMENTAL BIOLOGY
Resource
DNA material 8xGT-IIC-LucII (RDB08067) pCMV-Flag-Tead1 (RDB012170) pCMV-Flag-Tead2 (RDB012171) pMYs-Tead1-VP16-IRES-EGFP (RDB012172) pMYs-Tead2FL-IRES-EGFP (RDB012173) pMYs-Tead2-VP16-IRES-EGFP (RDB012174) pMYs-Tead2-EnR-IRES-EGFP (RDB012175) pMYs-Tead4-VP16-IRES-EGFP (RDB012176) pMYs-HA-Yap1-IRES-EGFP (RDB012177) pMYs-HA-Yap1 DTead BD-IRES-EGFP (RDB012178) pMYs-HA-Yap1 DWW-IRES-EGFP (RDB012179) pMYs-HA-Yap1 DAD-IRES-EGFP (RDB012180) pMYs-HA-Yap1 S112A-IRES-EGFP (RDB012181) pMYs-HA-dnYap1-IRES-EGFP (RDB012182)