Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis.

The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated.

A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death.

Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial cadherin (VE-cadherin) and upregulation of mesenchymal genes such as those for fibronectin and Snail1/2. In these cells, transforming growth factor β1 exacerbates Notch effects by increasing Snail1 and fibronectin activation.

Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6.

The Wnt canonical ligands elicit the activation of β-catenin transcriptional activity, a response dependent on, but not limited to, β-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex.

Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability.

The zinc finger transcription factor Snail1 regulates epithelial to mesenchymal transition, repressing epithelial markers and activating mesenchymal genes. Snail1 is an extremely labile protein degraded by the cytoplasmic ubiquitin-ligases β-TrCP1/FBXW1 and Ppa/FBXL14. Using a short hairpin RNA screening, we have identified FBXL5 as a novel Snail1 ubiquitin ligase.

The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation.

The transcription factor SNAIL1 is a master regulator of epithelial to mesenchymal transition. SNAIL1 is a very unstable protein, and its levels are regulated by the E3 ubiquitin ligase beta-TrCP1 that interacts with SNAIL1 upon its phosphorylation by GSK-3beta. Here we show that SNAIL1 polyubiquitylation and degradation may occur in conditions precluding SNAIL1 phosphorylation by GSK-3beta, suggesting that additional E3 ligases participate in the control of SNAIL1 protein stability.

Snail1 down-regulation using small interfering RNA complexes delivered through collagen scaffolds.

Control of gene expression via small interfering RNA has enormous potential for the treatment of a variety of diseases, including cancer and Huntington's disease. However, before any therapies can be developed, effective techniques for controlled delivery of these molecules must be devised. In this proof-of-concept study, small interfering RNA was complexed with a polymer and loaded into a biomaterial scaffold.