69 research outputs found

    Modulation of the Ξ²-Catenin Signaling Pathway by the Dishevelled-Associated Protein Hipk1

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    BACKGROUND:Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY:We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS:These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation

    Contesting the rule of law: civil society and legal institutions

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    This book examines the ambiguous role played by civil society in state-building, democratisation and post-conflict reconstruction in the Western Balkans. In doing so, it challenges the received wisdom that civil society is always a force for good. Civil society actors have helped create the conditions for new, more constructive relations inside and between former Yugoslav countries. But, their agency has also rekindled nationalism hindering efforts to rebuild the region after the conflicts of the 1990s. The book demonstrates that diverse civil society effects cannot be captured without querying both the nature of civil society and the complexity of the ongoing transformation. So how can the emancipatory role of civil society be harnessed? This rigorous case study-driven reappraisal of the ability of civil society to support progressive transformation from an illiberal regime to democracy and from conflict to peace will be a valuable resource to scholars and practitioners alike
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