Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: Receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: An early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain

Unlocking the potential of urban forests : developing a local urban forestry action plan

Project title: Uforest. Uforest is a three-year Knowledge Alliance project co-funded by the Erasmus+ Programme of the European Commission. The project and alliance aim at promoting Europe's innovation capacity among universities, cities and businesses to deliver a new approach to Urban Forestry.In recent years, urban forestry has increasingly caught the attention of policymakers and politicians as a nature-based approach to tackling some of our key societal challenges. These include the impact of climate change, biodiversity loss, urban densification, the demand for forest products and the health and recreation needs of urban populations. Furthermore, urban forestry offers potential to deliver key aspects of European Union (EU) policies such as the New Green Deal, the EU Biodiversity Strategy and the EU Urban Agenda. This document aims to increase awareness about urban forestry, the numerous and diverse benefits that it can provide and practical steps for developing an Urban Forestry Action Plan at a local level. In this respect, the multifunctionality of urban forestry and the cross-cutting outputs and services that it can deliver must be considered one of its greatest strengths