Caspase-3 Cleavage Links δ-Catenin to the Novel Nuclear Protein ZIFCAT

Gu, Dongmin; Tonthat, Nam K.; Lee, Moon-Sup; Ji, Hong; Bhat, Krishna; Hollingsworth, Faith; Aldape, Kenneth; Schumacher, Maria A.; Zwaka, Thomas P.; McCrea, Pierre D.

doi:10.1074/jbc.m110.167544

Cited by 16 publications

(17 citation statements)

References 67 publications

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“…Given its cytoplasmic localization, it is likely that CASP7 plays an indirect role in E-cadherin transcription. Interestingly, a recent report revealed that CASP3-induced cleavage of δ-catenin generates a fragment that localizes to the nucleus and binds to a zinc finger transcriptional factor (ZIFCAT), potentially modulating its function (35). We speculate that CASP7 might exhibit a similar role and process unknown factor(s) that modulate E-cadherin transcription in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a post-transcriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through post-transcriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT.

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Section: Discussionmentioning

confidence: 99%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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“…The p120 catenin subfamily member δ-catenin can bind to and modulate the activity of the WNT pathway transcriptional factor LEF 107 and the repressor Kaiso 108 , as well as the novel Krab-domain zinc-finger transcriptional repressor ZIFCAT 109 , the gene targets and biological roles of which are not yet established. As δ-catenin binds to ZIFCAT in its zinc-finger domain, it might compete ZIFCAT away from DNA and thereby enable gene activation through derepression.…”

Section: Other Armadillo Catenins In the Nucleusmentioning

confidence: 99%

Beyond β-catenin: prospects for a larger catenin network in the nucleus

McCrea

Gottardi

2015

Nat Rev Mol Cell Biol

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120

108

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β-catenin is widely regarded as the primary transducer of canonical WNT signals to the nucleus. In most vertebrates, there are eight additional catenins that are structurally related to β-catenin, and three α-catenin genes encoding actin-binding proteins that are structurally related to vinculin. Although these catenins were initially identified in association with cadherins at cell–cell junctions, more recent evidence suggests that the majority of catenins also localize to the nucleus and regulate gene expression. Moreover, the number of catenins reported to be responsive to canonical WNT signals is increasing. Here, we posit that multiple catenins form a functional network in the nucleus, possibly engaging in conserved protein–protein interactions that are currently better characterized in the context of actin-based cell junctions.

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“…In vitro binding assays were performed as described previously (Gu et al, 2011). In brief, proteins were synthesized using the TNT SP6 high-yield wheat germ protein expression system (Promega).…”

Section: In Vitro Neuronal Differentiationmentioning

confidence: 99%

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Lee

Furuta

et al. 2014

Journal of Cell Science

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Although the canonical Wnt pathway and b-catenin have been extensively studied, less is known about the role of p120-catenin (also known as d1-catenin) in the nuclear compartment. Here, we report that p120-catenin binds and negatively regulates REST and CoREST (also known as Rcor1), a repressive transcriptional complex that has diverse developmental and pathological roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos and in vitro systems, we find that p120-catenin directly binds the REST-CoREST complex, displacing it from established gene targets to permit their transcriptional activation. Importantly, p120-catenin levels further modulate the mRNA and protein levels of Oct4 (also known as POU5F1), Nanog and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this new p120-catenin-REST-CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces signals between Ecadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator and/or pathway regulating REST-CoREST, and reveal a substantial role for p120-catenin in the modulation of stem cell differentiation.

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Caspase-3 Cleavage Links δ-Catenin to the Novel Nuclear Protein ZIFCAT

Cited by 16 publications

References 67 publications

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Beyond β-catenin: prospects for a larger catenin network in the nucleus

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

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