The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

A quantitative proteomics tool to identify DNA-protein interactions in primary cells or blood

Contains fulltext : 140024.pdf (Publisher’s version ) (Closed access

A covalent and cleavable antibody-DNA conjugation strategy for sensitive protein detection via immuno-PCR

Contains fulltext : 156910.pdf (publisher's version ) (Open Access

The SMAD2/3 interactome reveals that TGF beta controls m(6)A mRNA methylation in pluripotency

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A polymorphic enhancer near grem1 influences bowel cancer risk through differential cdx2 and tcf7l2 binding

Contains fulltext : 131550.pdf (publisher's version ) (Open Access

Resources for proteomics in mouse embryonic stem cells.

no Abstract

Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II).

Item does not contain fulltextContext: Inactivating mutations within the AR-gene are present in only around 40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR-gene mutation negative group of AIS-individuals with compromised AR-function (AIS type II). Objective: To investigate if AIS type II can be due to epigenetic repression of AR-transcription. Design: Quantification of AR-mRNA and AR proximal promoter CpG-methylation levels in genital skin derived fibroblasts (GF) derived from AIS type II individuals and control individuals. Setting: University Hospital endocrine research laboratory. Patients: GF from control individuals (N=11) and AIS type II individuals (N=14). Intervention(s): None. Main Outcome Measure(s): Measurement of AR-mRNA and AR promoter CpG-methylation as well as activity of AR proximal promoter in vitro. Results: 57% of individuals with AIS type II (N=8) show a reduced AR-mRNA expression in their GF. A significant inverse correlation exists between AR-mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158bp long region containing these CpGs is sufficient to severely reduce reporter gene expression. This region is bound by the Runt Related transcription factor1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells is able to inhibit reporter gene expression through this region. Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR-gene expression and may result in AIS type II. We suggest that transcriptional modifiers, like RUNX1, could play roles therein offering new perspectives for understanding androgen-mediated endocrine diseases

Traitements intrapéritonéaux de la carcinose ovarienne : proposition d’algorithmes décisionnels [Intraperitoneal therapy for carcinomatosis in ovarian cancer: proposed treatment algorithm]

Ovarian cancer is the first cause of death by gynecological cancer. Most of the patients are diagnosed with peritoneal carcinomatosis that represents a therapeutic challenge. Its management implies maximal cytoreductive surgery with survival benefit. Over the last three decades, several strategies of intra-peritoneal chemotherapy have been investigated. This includes intra-peritoneal adjuvant chemotherapy that is used mainly in North America, hyperthermic intraperitoneal chemotherapy (HIPEC) and more recently pressurized intraperitoneal aerosol chemotherapy (PIPAC). In the current article, we review the evidence in favor of each therapeutic approach, and we propose treatment algorithms depending on the clinical situation of ovarian cancer patients: upfront, platinum-sensitive and platinum-resistant relapse