Characterization of the SNAG and SLUG Domains of Snail2 in the Repression of E-Cadherin and EMT Induction: Modulation by Serine 4 Phosphorylation

Snail1 and Snail2, two highly related members of the Snail superfamily, are direct transcriptional repressors of E-cadherin and EMT inducers. Previous comparative gene profiling analyses have revealed important differences in the gene expression pattern regulated by Snail1 and Snail2, indicating functional differences between both factors. The molecular mechanism of Snail1-mediated repression has been elucidated to some extent, but very little is presently known on the repression mediated by Snail2. In the present work, we report on the characterization of Snail2 repression of E-cadherin and its regulation by phosphorylation. Both the N-terminal SNAG and the central SLUG domains of Snail2 are required for efficient repression of the E-cadherin promoter. The co-repressor NCoR interacts with Snail2 through the SNAG domain, while CtBP1 is recruited through the SLUG domain. Interestingly, the SNAG domain is absolutely required for EMT induction while the SLUG domain plays a negative modulation of Snail2 mediated EMT. Additionally, we identify here novel in vivo phosphorylation sites at serine 4 and serine 88 of Snail2 and demonstrate the functional implication of serine 4 in the regulation of Snail2-mediated repressor activity of E-cadherin and in Snail2 induction of EMT

AKT2 interacts with Snail1 in the E-cadherin Promoter

12 p.-7 fig.Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.Oncogene advance online publicationThis study was supported by grants awarded by the Ministerio de Ciencia e Innovación (BFU2006-03203 and BFU2009-07578 to MD and SAF2006-00339 and SAF2010-16089 to AGH) and Fundació La Marató de TV3 (to AGH). The partial support from the Instituto Carlos III-Fondos FEDER (RTICCC, C03710, RD06/0020/0040) and the Generalitat de Catalunya (2009SGR867) is also appreciated. PV and RV-C were supported by predoctoral fellowships from the Ministerio de Ciencia y Tecnología and Instituto Carlos III, respectivel

Architectural regeneration and its theoretical context

Cycles of decline and rejuvenation, and the adaptation and re-use of buildings, have been common constants of the built environment throughout the history of human settlement. The more formalised practices of building conservation and regeneration on the other hand are an outcome of movements that emerged in the nineteenth century, which were informed by theoretical standpoints that were products of the post-Enlightenment positivist, rational and romantic outlooks (Gelernter 1995). Some of these theories and standpoints continue to inform interventions in the built environment, while others have been eclipsed by alternative worldviews and environmental realities. Architectural regeneration as a notion and as a distinct discipline emerges from a number of those concurrent, symbiotic, complementary and sometimes conflicting theories. The purpose of this chapter is to position architectural regeneration into its theoretical context and to demonstrate how it continues to be informed by a range of contemporary philosophies. Worldwide, laws, policy and guidance concerning the protection and conservation of historic buildings have come to be based on a set of principles that have emerged from an international conservation movement that can be traced back to Eurocentric philosophies of the nineteenth century (Jokilehto 1999). The design of the urban realm, buildings and interiors meanwhile are regularly discussed and critiqued in the context of prevalent design theories which in the latter half of the twentieth century were deliberately separated from theories pertaining to the conservation of historic buildings. The processes of adaptive re-use, which architectural regeneration encompasses, can be seen simultaneously as part of the collective theoretical frameworks of conservation and design, and also outside of them. Although ‘architects have led the conservation world in matters of principles and philosophy’ (Muñoz Viñas 2011: 71), they have also been instrumental in de-coupling conservation from design. Architectural regeneration has emerged in this middle ground between conservation and architectural design. At the same time, the broader realm of regeneration is often positioned in the domain of policy, spatial planning and economic development. Growing environmental concerns and climate change awareness are driving innovation in multiple arenas, including urban planning and building design. The current environmental crisis has become one of the key drivers for making better use of existing resources as well as for buildings to adapt to respond to new realities (Leatherbarrow and Wesley 2018). Starting from the latter part of the twentieth century there have been an increasing number of publications on the subject of adaptive re-use. Nonetheless, a shared and accepted vocabulary and definition of what adaptive reuse is, and what it involves, remains ambiguous, with various terminologies and definitions prevailing (Plevoets and Van Cleempoel 2013: 13). The same ambiguity applies to regeneration more generally. One of the earliest books on the subject of re-use is Sherban Cantacuzino’s New Uses for Old Buildings, published in 1975. The content, as that of many others that have been published since, is prescriptive and focuses on potential new uses linked to building typologies. Many of the volumes that have followed have remained technical (Eley and Worthington 1984; Highfield 1987) and heavily depend on case studies that are used to exemplify the processes, practicalities and design potential of re-use (Austin et al. 1988; Larkham 2000; Morrison and Waterson 2019). A new perspective was introduced by Stewart Brand in his book How Buildings Learn, published in 1997, where the value of built-in flexibility is upheld as a characteristic conducive to easy adaptability and a long use-span for buildings. There remains, however, a theoretical vacuum framing the subject, which this chapter intends to redress. The chapter consists of two sections. In the first section we examine the various theories within which architectural regeneration is contextualised, and the second proposes a number of key principles that inform the processes of architectural regeneration