Expression of Constitutively Active CDK1 Stabilizes APC-Cdh1 Substrates and Potentiates Premature Spindle Assembly and Checkpoint Function in G1 Cells

Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more subtle type of defect in activity of the APC-driven negative-feedback loop may have implications for triggering genome instability and tumorigenesis

Anisotropic diffusion of water molecules in hydroxyapatite nanopores

Funded by EPSRC Grant EP/K000128/1

COUP-TFII Controls Mouse Pancreatic β-Cell Mass through GLP-1-β-Catenin Signaling Pathways

Background: The control of the functional pancreatic beta-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how beta-cell mass is determined

EPR study of Yb-doped irradiated glasses

International audienceYb3+ reduction under β and γ irradiation has been studied in aluminoborosilicate glasses by EPR spectroscopy. From the Yb3+ EPR line variation, we demonstrate that more than one Yb3+ sites coexist in the pristine Yb-doped glasses. Reduction of Yb3+ into Yb2+ is observed for all integrated doses and Yb doping contents. For doses higher than 108 Gy, an Yb3+ ion environment change occurs, this change is correlated with a stabilization of the reduced Yb2+ state. The paramagnetic defect concentration displays a linear variation as a function of the logarithm of the dose. The glass doping with Yb2O3 leads to a substantial decrease of the defect concentration as well as a modification in the relative proportion of the defects produced. In particular, Yb doping tends to increase the relative content of Oxy defect

LA SÉDIMENTATION LAGUNAIRE DES DERNIERS SIÈCLES EN LANGUEDOC-ROUSSILLON. DONNÉES SÉDIMENTOLOGIQUES, ISOTOPIQUES ET PALYNOLOGIQUES

International audienc

Antibody-mediated catalysis: Induction and therapeutic relevance

Abzymes are immunoglobulins endowed with enzymatic activities. The catalytic activity of an abzyme resides in the variable domain of the antibody, which is constituted by the close spatial arrangement of amino acid residues involved in catalysis. The origin of abzymes is conferred by the innate diversity of the immunoglobulin gene repertoire. Under deregulated immune conditions, as in autoimmune diseases, the generation of abzymes to self-antigens could be deleterious. Technical advancement in the ability to generate monoclonal antibodies has been exploited in the generation of abzymes with defined specificities and activities. Therapeutic applications of abzymes are being investigated with the generation of monoclonal abzymes against several pathogenesis-associated antigens. Here, we review the different contexts in which abzymes are generated, and we discuss the relevance of monoclonal abzymes for the treatment of human diseases

The migration of beech ( Fagus sylvatica L.) up the Rhone: the Mediterranean history of a “mountain” species

http://dx.doi.org/10.1007/s00334-005-0068-9International audienceNew anthracological data on the beech (Fagus sylvatica L.), obtained through rescue excavations, allows the proposal of a new pattern of population by beech of the South of France since the Lateglacial. Due to itscurrent ecology and distribution it is considered to be a mountain species in the Mediterranean area despite the presence of beech forests, usually described as glacial relicts, at low altitudes in the South of France and in the Rhone valley (Sainte-Baume, Valbonne and Grand Fays). Our results, combined with previous pollen and charcoal data, show both an early spread from glacial refuges and a late disappearance of the species. During the glacial period, the beech remained in the southernmost zones. From there, it first spread during the Preboreal towards outposts in the Rhone delta, and during the Atlantic along the rhodanian corridor. During the Subboreal, a retreat of beech towards the Pre-Alps and the Rhone delta can be traced. The Iron Age and the Classical period experienced the maximal concentration of beech along the Rhone river, while it became more rare in the North and in the South. During the Middle Ages, it first disappeared from these distal areas, and later also in the valley (around A.D.1000), finally settling in its present mountainous distribution area (probably around the 14th century A.D.). Some crucial points of the proposed dynamics are further analysed: the paradoxical regression of beech in the valley during the Subboreal, the factors determining the expansion of beech from refuge areas during the Subatlantic and finally, the disappearance of the beech in the middle Rhone valley in rather recent times, a disappearance attributed to the strong human impact on the landscape.Les nouvelles données anthracologiques concernant le hêtre (Fagus sylvatica L.), obtenues grâce au développement de l'archéologie préventive, permettent de proposer un nouveau modèle de diffusion de cette espèce depuis le Tardiglaciaire. D'après son écologie et sa distribution actuelles, elle est considérée comme une espèce montagnarde dans la région méditerranéenne, en dépit de la présence de hêtraies, souvent envisagées comme des reliques glaciaires, à basse altitude dans le sud de la France et dans la vallée du Rhône (Sainte-Baume, Valbonne et le Grand Fays). Nos résultats, combinées aux données polliniques et anthracologiques préexistantes, montrent une diffusion précoce à partir des refuges glaciaires, et une disparition tardive de cette espèce. Au cours de la période glaciaire, le hêtre s'est maintenu dans les zones les plus méridionales, puis s'est diffusé au cours du Préboréal, à partir d'avant-postes localisés dans le delta du Rhône, et au cours de l'Atlantique le long du couloir rhodanien avant de se replier vers les Préalpes et le delta du Rhône au Subboréal. L'Âge du Fer et l'Antiquité connaissent la concentration maximale du hêtre le long du Rhône, alors qu'il se raréfie au nord et au sud de la zone. Au Moyen Âge, il disparaît tout d'abord de ces zones distales, et ensuite de la vallée (vers 1000 A.D.), pour s'installer définitivement dans sa zone de répartition actuelle (probablement autour du 14eme siècle). Quelques points cruciaux de la dynamique de peuplement sont analysés : la régression paradoxale du hêtre dans la vallée au Subboréal, le déterminisme de son expansion à partir des zones refuges au cours du Subatlantique et, finalement, sa disparition de la moyenne vallée du Rhône à une période récente, disparition attribuée à la forte emprise humaine sur le paysage