TCF Is the Nuclear Effector of the β-Catenin Signal That Patterns the Sea Urchin Animal–Vegetal Axis

Vonica, Alin; Weng, Wei; Gumbiner, Barry M.; Venuti, Judith M.

doi:10.1006/dbio.1999.9551

Cited by 132 publications

(96 citation statements)

References 58 publications

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“…CHOP inhibits Wnt signalling M Horndasch et al site, Vonica et al, 2000) dose-dependently decreased the frequency of secondary axes (Figure 2d). These data suggest that CHOP inhibits the canonical Wnt pathway downstream of b-Catenin, most likely at the level of transcription.…”

Section: Chop Inhibits Dorsal Embryonic Structures In Xenopus Embryosmentioning

confidence: 77%

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The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

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Section: Chop Inhibits Dorsal Embryonic Structures In Xenopus Embryosmentioning

confidence: 77%

“…hTCF-4 was a gift from H Clevers. Mutant b-Catenin pcDNA3 was a gift from Dr McCormick and TCF-VP16 was described in Vonica et al (2000). Reporter constructs TopFlash and FopFlash were obtained from upstate (NY, USA).…”

Section: Plasmid Constructsmentioning

confidence: 99%

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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“…␤-Catenin fused to the engrailed repressor domain chimera (␤-cat/ engrailed) potently inhibits ␤-catenin/TCF-mediated transcription and a form of TCF fused to the potent VP16 transactivation domain (VP16/TCF) is constitutively active (Montross et al, 2000;Vonica et al, 2000). Neither of the constructs had any effect on the growth of HT29 or MCF-7 cells or on the cell growth inhibition induced by E-cadherin ligation at the surface of HT29 and MCF-7 cells ( Figure 6A).…”

Section: Specific Engagement Of E-cadherin Inhibits Cell Growth By a mentioning

confidence: 99%

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

Perrais

Chen

Pérez-Moreno

et al. 2007

MBoC

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193

178

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E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to ␤-catenin is required for cell growth inhibition, but ␤-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor ␤-catenin binding to ␣-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a ␤-catenin-dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a ␤-catenin-dependent mechanism that inhibits selective signaling functions of growth factor receptors. INTRODUCTIONCell-cell adhesion mediated by cadherins is fundamental for the differentiation and integrity of most adult tissues (Gumbiner, 1996(Gumbiner, , 2005. E-cadherin is a major constituent of polarized epithelial cell junctions, and it mediates cell adhesion through Ca 2ϩ -dependent homophilic interaction of its extracellular domain and interaction of its cytoplasmic domain with catenins. E-cadherin is also a tumor suppressor protein, because its loss of expression or function has been shown to be associated with tumorigenesis and tumor progression (Takeichi, 1993). Restoration of E-cadherin expression in cancer cells results in decreased invasiveness, growth suppression, and terminal differentiation (Behrens et al., 1989;Vleminckx et al., 1991;Perl et al., 1998;Gottardi et al., 2001;Wong and Gumbiner, 2003).Cadherins have also been postulated to be responsible for the phenomenon of contact inhibition of cell growth. Contact inhibition is a widely acknowledged property of cells in tissue , but the mechanisms that are responsible are not well understood. Although, there is evidence that cadherin expression can influence cell growth rates (Watabe et al., 1994;Caveda et al., 1996;St Croix et al., 1998;Mueller et al., 2000;Motti et al., 2005), their exact roles in contact inhibition are not well understood. A density-dependent inhibition of cell proliferation could result from many other factors that are indirectly influenced by the...

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“…Activating or inhibiting the Wnt pathway had a dramatic effect on FGF20 and DKK1 expression. We injected RNA encoding an activated form of the downstream component of the pathway (VP16Xtcf-3) or a dominant-negative mutant (DNXtcf-3) (Vonica et al, 2000) into the equatorial zone of each blastomere at the four-cell stage ( Figure 3C). XFGF20 and Xdkk-1 RNAs were increased by VP16Xtcf-3, and undetectable when Wnt signaling was blocked with DNXtcf-3RNA.…”

Section: Genes Regulated By Mutant B-catenin In a Human Epithelial Cementioning

confidence: 99%

FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development

Chamorro

Schwartz

Vonica

et al. 2004

EMBO J

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290

219

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b-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize b-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated b-catenin in a human epithelial cell line (293) engineered to produce mutant b-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/b-catenin pathway. Two genes strongly induced in both systems-FGF20 and DKK1-were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the Apc Min allele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for b-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by b-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.

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TCF Is the Nuclear Effector of the β-Catenin Signal That Patterns the Sea Urchin Animal–Vegetal Axis

Cited by 132 publications

References 58 publications

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development

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