Stéphanie Bouillot

The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis

Vascular endothelial (VE)-cadherin is exclusively expressed at interendothelial junctions of normal and tumour vessels. In this report, we characterized the transcriptional activity of the human VE-cadherin promoter. Transient transfection assays revealed that sequences at positions −1135/−744 and −166/−5 base pairs are critical for promoter activity in endothelial cells. We show that specific sequences in the proximal region interact with Ets and Sp1 family members. Transgenic mice were created and the human VE-cadherin promoter was able to confer correct temporal and spatial expression on the LacZ gene in embryos. In adults, the transgene was specifically and strongly expressed in the lung, heart, ovary, spleen and kidney glomeruli, whereas expression was weak or absent in the vasculature of other organs, including the brain, thymus, liver and skeletal muscle. Neovessels in tumour grafts and Matrigel implants harboured strong stainings, indicating that promoter activity is enhanced in angiogenic situations. Furthermore, Matrigel and transfection assays showed that VE-cadherin promoter is subjected to bFGF induction. Transgene expression was also noticed in extravascular sites of the central nervous system, suggesting that silencer elements may be located elsewhere in the gene. These results are a first step towards addressing the organ- and tumour-specific regulation of the VE-cadherin gene.

Structural Basis of Cytotoxicity Mediated by the Type III Secretion Toxin ExoU from Pseudomonas aeruginosa

The type III secretion system (T3SS) is a complex macromolecular machinery employed by a number of Gram-negative pathogens to inject effectors directly into the cytoplasm of eukaryotic cells. ExoU from the opportunistic pathogen Pseudomonas aeruginosa is one of the most aggressive toxins injected by a T3SS, leading to rapid cell necrosis. Here we report the crystal structure of ExoU in complex with its chaperone, SpcU. ExoU folds into membrane-binding, bridging, and phospholipase domains. SpcU maintains the N-terminus of ExoU in an unfolded state, required for secretion. The phospholipase domain carries an embedded catalytic site whose position within ExoU does not permit direct interaction with the bilayer, which suggests that ExoU must undergo a conformational rearrangement in order to access lipids within the target membrane. The bridging domain connects catalytic domain and membrane-binding domains, the latter of which displays specificity to PI(4,5)P2. Both transfection experiments and infection of eukaryotic cells with ExoU-secreting bacteria show that ExoU ubiquitination results in its co-localization with endosomal markers. This could reflect an attempt of the infected cell to target ExoU for degradation in order to protect itself from its aggressive cytotoxic action.

Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice†

Fibrillin‐1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin‐1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin‐1 deficiency could also contribute to late‐onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3‐week‐old, 6‐month‐old, and 24‐month‐old mice that are heterozygous for a hypomorphic structural mutation of fibrillin‐1 (Fbn1

VE-cadherin cleavage by LasB protease from Pseudomonas aeruginosa facilitates type III secretion system toxicity in endothelial cells.

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Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein EVIDENCE OF SHEDDING UP-REGULATION IN PRE-ECLAMPSIA

mice). Our results indicate that Fbn1

Phenotype and toxicity of the recently discovered exlA‐positive Pseudomonas aeruginosa strains collected worldwide

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Protocadherin-12 deficiency leads to modifications in the structure and function of arteries in mice

mice, particularly those that are 24 months old, are slightly more hypotensive than wild‐type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing Fbn1

Pseudomonas aeruginosa Pore-Forming Exolysin and Type IV Pili Cooperate To Induce Host Cell Lysis

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Pseudomonas aeruginosa Transmigrates at Epithelial Cell-Cell Junctions, Exploiting Sites of Cell Division and Senescent Cell Extrusion

mice than in the wild‐type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1

Pseudomonas aeruginosa Exolysin promotes bacterial growth in lungs, alveolar damage and bacterial dissemination

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