Api5 : un nouveau co-facteur du récepteur aux oestrogènes ERalpha impliqué dans la progression tumorale des carcinomes mammaires

La recherche de nouveaux facteurs pronostiques et les nouvelles cibles thérapeutiques sont en plein essor et présentent de nouveaux espoirs en ce qui concerne la prise en charge et la thérapie ciblée dans le cancer du sein. Depuis longtemps l'expression du récepteur aux œstrogènes (ER) représente l'un des principaux facteurs de pronostic et constitue avec les œstrogènes une cible thérapeutique incontournable. Les co-régulateurs de l'ER sont souvent dérégulés et participent ainsi, si ce n'est à la genèse du cancer, du moins à son développement ainsi qu'aux mécanismes cellulaires d'échappement thérapeutique. Ainsi, une meilleure connaissance de ces molécules pourrait apporter un bénéfice dans la prise en charge des patients. De plus étant situé en amont de la voie transcriptionnelle, leur ciblage permettrait d'atteindre simultanément plusieurs voies de signalisation et pourrait permettre d'empêcher les cellules de développer des mécanismes de résistance. Nous présentons dans ce travail un nouveau co-régulateur d'ER : Api5 qui est reconnu comme un facteur anti-apoptotique. Nous avons analysé l'expression d'Api5 dans les carcinomes mammaires par une étude immunohistochimique prospective et nous avons montré que la perte d'Api5 était associée à des facteurs de mauvais pronostic et qu'il était co-localisé avec ERa. Nous avons aussi montré que sa présence était nécessaire à la croissance tumorale. Nous avons constaté qu'Api5 régulait la transcription de gènes dépendant du ERa en se fixant sur l'ADN sur ses éléments de réponse (ERE) ou indirectement en interagissant avec la protéine activatrice 1 (Activator proteine 1 : AP1). Enfin, nous avons observé que la séquence LXXLL d'Api5 était nécessaire à la liaison directe entre Api5 et le domaine C d'ERa. Cette étude décrit pour la première fois l'expression immunohistochimique d'Api5 dans des cancers et caractérise les relations fonctionnelles et physiques liant Api5 à l'ERa. Nous proposons donc Api5 comme un nouveau co-facteur de l'ERa, pouvant potentiellement représenter une nouvelle cible thérapeutique des cancers du sein.New prognostic markers and molecular targets are currently developing and represent new hopes concerning patient's management and target therapies in breast cancer. Estrogen receptor is known for a long time to be one of the major prognostic markers and is with estrogen the basic target for therapy. Co-regulators of estrogen receptor are often misexpressed. Rather than playing a causal role in the genesis of cancer they provide the potential for amplification of temporal disease progression. They are also able to counteract the biological activities of therapeutic drugs. In consequence, a greater understanding of these co-regulators master genes should prove to be beneficial to the diagnosis and therapy of cancer. Moreover, these co-regulators are upstream the signaling pathway of many transcriptional factors such as ERa. Consequently, inhibition of one oncogenic co-activator could simultaneously silence a cadre of downstream genes, which, together, are responsible for the accelerated growth of the oncogenic cell and could prevent acquired therapeutic resistance. We present in this work a new co-regulator of estrogen receptor: Api5, which is known as an anti-apoptotic protein. We explored Api5 expression in breast cancer by a prospective immunohistochemical study and showed that the loss of Api5 was associated with bad prognosis factor and that it co-localized with ERa in breast carcinomas. We also showed that its presence was necessary for tumor growth. We observed that Api5 regulates ERa signaling on downstream target genes on ERE and AP1sites. We also observed that Api5 facilitates ERa recruitment onto its target promoters. Finally we demonstrated that Api5 LXXLL domain is necessary for its interaction with ERa and we showed a direct interaction between Api5 and the ERa DNA binding domain (DBD). This is the first study that describes Api5 expression by immunohistochemistry in tumors and that demonstrates the functional and physical relationship connecting Api5 to ERa suggesting Api5 as a major cofactor of ERa signalization

E2F1 activates p53 transcription through its distal site and participates in apoptosis induction in HPV-positive cells

AbstractThe p53 tumor suppressor protein, one of the most extensively studied proteins, plays a pivotal role in cellular checkpoints that respond to DNA damage to prevent tumorigenesis. However, the transcriptional control of the p53 gene has not been fully characterized. We report that the transcription factor E2F1 binds only to the E2F1 distal site of the p53 promoter in the human papillomavirus positive carcinoma HeLa cell line. Moreover, we showed that etoposide, a DNA damaging agent, activates p53 transcription through the E2F1 pathway. This increase correlates with apoptosis induction as disruption of this pathway led to reduced apoptosis stimulation by the DNA damaging agent

Operationalising emission and toxicity modelling of pesticides in LCA: the OLCA-Pest project contribution

Purpose Current field emission modelling and toxicity characterisation of pesticides suffer from several shortcomings like mismatches between LCI databases and LCIA methods, missing characterisation factors, missing environmental compartments, and environmental impact pathways. The OLCA-Pest project was implemented to address these aspects and to operationalise the assessment of pesticides in LCA. Based on this effort, we propose an approach to integrate pesticide emissions into LCI databases. Methods The PestLCI Consensus Model has been developed in order to estimate emission fractions to different environmental compartments. The initial distribution fractions should be linked to the compartments air, agricultural soil, natural soil, and freshwater. Emissions to off-field surfaces are hereby distributed between agricultural soil, natural soil, and freshwater by using surface cover data. Deposition on the crop surface should be recorded in an emission compartment crop with 13 sub-compartments for crop archetypes for both food and non-food uses. Default emission fractions are provided to calculate the emission fractions for different pesticide application scenarios. Results and discussion A sensitivity analysis shows the effects of the application technique, drift reduction, crop and development stage, field width, and buffer zone on the initial distribution fractions of field-applied pesticides. Recommendations are given for the implementation of a set of default initial distribution fractions into LCI databases, for the organisation of metadata, and for the modelling of pesticide residues in food along the supply chain (processing, storage). Priorities for further research are: improving the modelling of pesticide secondary emissions, further extending emission modeling (e.g. additional application techniques, including cover crops), considering metal-based pesticides in emission models, and systematically assessing human health impacts associated with pesticide residues in food crops. Conclusions The proposed approach allows to preserve the mass balance of the pesticide emitted after application, to make a consistent assessment of ecotoxicity and human toxicity, to define a clear and consistent interface between the LCI and LCIA phases, to estimate initial emission distribution fractions based on existing data, to document metadata transparently and efficiently within crop datasets, and to model the removal of pesticide residues in food during processing.info:eu-repo/semantics/publishedVersio

Synthèse et caractérisation de nouveaux complexes aryloxy à base de tungstène

International audienc

Predicting bee community responses to land-use changes: Effects of geographic and taxonomic biases

Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises

Maladie de Creutzfeldt-Jakob sporadique (corrélations entre la neuropathologie, la clinique et le génotype de 17 cas)

Il est reconnu que le polymorphisme du codon 129 Méthionine/Valine joue un rôle important dans la variabilité des présentations phénotypiques des Maladies de Creutzfeldt-Jakob sporadiques (MCJs). L'objectif de ce travail était d'étudier les corrélations entre la neuropathologie, la clinique et le génotype de 17 cas de MCJs. Le matériel prélevé dans 11 régions du cerveau a été analysé au microscope optique en coloration standard et en immunohistochimie (anti-protéine prion). Les signes neurologiques ont été recueillis dans les dossiers médicaux et auprès des cliniciens. Nos résultats montrent une corrélation par groupe génotypique entre les signes cliniques et les intensités des lésions dans les régions fonctionnelles correspondantes pour : l'aphasie, l'apraxie, la mémoire, le syndrome extra pyramidal, le syndrome frontal, le syndrome cérébelleux et les troubles visuels. Deux cas atypiques ont été mis en évidence : un patient MM2 et un patient MV1 avec des plaques de type kuru dans le cortex cérébral et cérébelleux...TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF