http://repub.eur.nl/res/aut/3208/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/22857/ 2011-02-09T00:00:00Z Objective: Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear β-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate β-catenin at tyrosine residues, which is thought to increase β-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of β-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design: A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous β-catenin gene was introduced. Results: This study provided in vivo evidence that β-cateninE654 is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the β-cateninE654 targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of βcatenin. Surprisingly, the expression of β-cateninE654 did not affect histological grade or induce tumour invasiveness. Conclusions: A thus far unknown mechanism was uncovered in which Y654 phosphorylation of β-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that β-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. http://repub.eur.nl/res/pub/5772/ 1997-01-01T00:00:00Z Hereditary frontotemporal dementia (HFTD) is a rare autosomal dominant form of presenile dementia characterized by behavioral changes and reduced speech. Three multigeneration kindreds with this condition, in the Netherlands, were investigated for clinicopathological comparison and linkage analysis. Frontotemporal atrophy on computed tomographic scanning and/or magnetic resonance imaging was usually present. Single-photon emission computed tomography (SPECT) showed frontal hypoperfusion in the early phase of the disease. Brain tissue showed moderate to severe atrophy of frontal and temporal cortex with neuronal loss, gliosis, and spongiosis. Pick bodies were lacking in all cases of the 3 families. The mean age of onset varied significantly between families. We report here evidence for linkage to chromosome 17q21-q22 with a maximum lod score of 4.70 at theta = 0.05 with the marker D17S932. Recombination analysis positions the gene for HFTD in a region of approximately 5 cM between markers D17S946 and D17S791. Three other neurodegenerative disorders with a strong clinical and pathological resemblance have recently been mapped to the same chromosomal region, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene. http://repub.eur.nl/res/pub/5812/ 1994-01-01T00:00:00Z In 31 symptomatic and 5 asymptomatic carriers of the amyloid precursor protein (APP) gene codon 693 mutation, 10 family members without mutation, and 5 carriers of the APP gene codon 692 mutation (3 with early-onset Alzheimer dementia, 2 with cerebral hemorrhage), a high frequency of the apolipoprotein E epsilon 4 allele was found. Age at onset, age at death, occurrence of dementia, and number of strokes did not differ between APP gene mutation carriers with or without epsilon 4 allele, showing that the clinical expression of these APP mutations is not influenced by the apolipoprotein E gene.