APCcdh1 Mediates Degradation of the Oncogenic Rho-GEF Ect2 after Mitosis

Background: Besides regulation of actin cytoskeleton-dependent functions, Rho GTPase pathways are essential to cell cycle progression and cell division. Rho, Rac and Cdc42 regulate G1 to S phase progression and are involved in cytokinesis. RhoA GDP/GTP cycling is required for normal cytokinesis and recent reports have shown that the exchange factor Ect2 and the GTPase activating protein MgcRacGAP regulate RhoA activity during mitosis. We previously showed that the transcription factors E2F1 and CUX1 regulate expression of MgcRacGAP and Ect2 as cells enter S-phase. Methodology/Principal Findings: We now report that Ect2 is subject to proteasomal degradation after mitosis, following ubiquitination by the APC/C complex and its co-activator Cdh1. A proper nuclear localization of Ect2 is necessary for its degradation. APC-Cdh1 assembles K11-linked poly-ubiquitin chains on Ect2, depending upon a stretch of,25 amino acid residues that contain a bi-partite NLS, a conventional D-box and two TEK-like boxes. Site-directed mutagenesis of target sequences generated stabilized Ect2 proteins. Furthermore, such degradation-resistant mutants of Ect2 were found to activate RhoA and subsequent signalling pathways and are able to transform NIH3T3 cells. Conclusions/Significance: Our results identify Ect2 as a bona fide cell cycle-regulated protein and suggest that its ubiquitination-dependent degradation may play an important role in RhoA regulation at the time of mitosis. Our findings raise the possibility that the overexpression of Ect2 that has been reported in some human tumors might result not only from deregulated transcription, but also from impaired degradation

Typicité sensorielle de vins de l'AOC Coteaux du Layon et acceptabilité par les acteurs (professionnels et consommateurs) de vins avec des titres d'alcool volumique plus faibles

In order to maintain an optimum sugar / acid balance in a changing context, winegrowers of the Coteaux du Layon PDO, a sweet wine of the middle Loire valley, wish to know if a final alcohol content (TAV) lower than the minimum imposed by the regulation of the PDO (11% vol. today) would affect the typicality of the wines. To answer this question, a study was carried out in 4 steps. 1) To know the expected typicality of these wines, focus groups were conducted with 26 professionals. 2) In order to assess the acceptability of lower TAV wines, based on a sample of 24 wines (commercial wines and experimental wines with TAV between 8% vol. and 10% vol.), 31 professionals scored levels of exemplarity. 3) A trained panel made a fine sensory description. 4) Finally, a selection of 8 wines from these 24 were evaluated by 163 consumers, they scored levels of preference. The results of steps 1) and 2) show a strong consensus among professionals to assess the exemplarity of wines. Experimental wines obtained exemplary scores above the average of the scale and can therefore be considered as good examples. In step 3), the trained panel generated the sensory attributes to describe the wines: 21 descriptors of odors and aromas and 6 of flavors, which reveal the sensory complexity of the wines. In stage 4), in general, the 8 wines evaluated by the consumers were all appreciated. The results suggest that a sufficiently high amount of residual sugar content would enhance the acceptability of lower TAV wines by both professionals and consumers. The winegrowers of the syndicate of Coteaux du Layon PDO thus have factual elements to update the specification of the PDO (decreasing the minimum TAV threshold), in interaction with INAO (the French national institute of origin and quality)

Saccharomyces boulardii CNCM I-745 Restores intestinal Barrier Integrity by Regulation of E-cadherin Recycling

International audienceAlteration in intestinal permeability is the main factor underlying the pathogenesis of many diseases affecting the gut, such as inflammatory bowel disease [IBD]. Characterization of molecules targeting the restoration of intestinal barrier integrity is therefore vital for the development of alternative therapies. The yeast Saccharomyces boulardii CNCM I-745 [Sb], used to prevent and treat antibiotic-associated infectious and functional diarrhea, may have a beneficial effect in the treatment of IBD

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

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DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL