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Le virus de Theiler, ou Theiler’s Murine Encephalomyelitis Virus (TMEV) est un picornavirus murin appartenant au genre Cardiovirus. Ce virus peut causer, dans certaines circonstances, une infection persistante du système nerveux central de la souris, caractérisée par des lésions démyélinisantes chroniques semblables à celles retrouvées dans la sclérose en plaques. Pour pouvoir persister, le virus doit s’opposer à la réponse immunitaire de l’hôte. La protéine Leader (L) du virus joue un rôle critique dans ce processus, notamment en bloquant la production de certaines cytokines et chimiokines produites en réponse à l’infection virale, comme les interférons de type I et RANTES. La protéine L provoque également une perturbation du trafic nucléocytoplasmique des protéines cellulaires, comme la protéine PTB. La mutation du doigt de zinc amino-terminal de la protéine affecte toutes ces fonctions.
Dans ce travail, nous avons montré que des mutations ponctuelle introduites dans le domaine carboxy-terminal de la protéine L affectent également ces fonctions de la protéine. Ce travail a donc contribué à définir un nouveau domaine critique pour l’activité de la protéine. Ce domaine est conservé chez l’ensemble des Theilovirus (TMEV, Saffold), mais est absent de la protéine L du virus EMCV. Par conséquent, nous l’avons appelé « theilo-domaine ».
Dans une deuxième partie de ce travail, nous avons montré que l’infection par TMEV déclenche l’apparition de granules de stress dans les cellules, mais que la formation de ces granules est inhibée par la protéine L. Ceci constitue une nouvelle fonction pour la protéine L du virus de Theiler.
Enfin, nous avons cherché à savoir, en utilisant des virus chimériques, si les protéines L de picornavirus récemment découverts et proches de TMEV partagent des fonctions communes avec la protéine L de TMEV. Des résultats préliminaires montrent que la protéine L du virus Saffold, un cardiovirus humain proche de TMEV, possède des fonctions semblables à celles de la protéine L de TMEV, notamment l’inhibition de la formation des granules de stress. De plus, une mutation du « theilo-domaine » de la protéine L du virus Saffold affecte l’activité de cette protéine Theiler’s Murine Encephalomyelitis Virus (TMEV) is a murine picornavirus belonging to the Cardiovirus genus. This virus can cause persistent infection of the central nervous system of the mouse, characterized by chronic demyelinating lesions similar to those found in multiple sclerosis. Antagonism of the host immune response is critical for viral persistence. The leader (L) protein of the virus plays an important role in this function, notably by blocking the production of cytokines and chemokines, such as type I interferons and RANTES. TMEV’s leader protein also perturbs nucleocytoplasmic trafficking of cellular proteins, such as PTB. Mutation of the N-terminal zinc-finger motif of the protein dramatically impairs these activities of the protein.
In this work, we have shown that point mutations introduced in the C-terminal domain of the L protein affect all of these functions. Thus, this work contributed to define a new critical domain for the activity of the L protein. This domain is conserved in the L protein of all Theiloviruses but is lacking in the L protein of EMCV. Accordingly, we called it “theilodomain”.
In a second part of this work, we have shown that infection of cells by Theiler’s virus triggers the formation of stress granules, but that this stress granules formation is blocked by the leader protein. This is a new function for the L protein of TMEV.
Finally, we tested, by constructing chimeric viruses, to what extent L proteins of recently discovered picornaviruses related to TMEV are functionnally interchangeables with TMEV’s L protein. Preliminary results show that L protein of Saffold virus, a human Cardiovirus closely related to TMEV, shares some activities with the L protein of TMEV, notably the antagonism of stress granules formation. Moreover, these activities are impaired when the conserved “theilo-domain” is mutated

Theilovirus --- Encephalomyocarditis virus --- Cell Aggregation --- Chemokine CCL5

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The number of males diagnosed with prostate cancer (PCa) is increasing all over the world. Most patients with early-stage PCa can be treated with appropriate therapy, such as radical prostatectomy or irradiation. On the other hand, androgen deprivation therapy (ADT) is the standard systemic therapy given to patients with advanced PCa. ADT induces temporary remission, but the majority of patients (approximately 60%) eventually progress to castration-resistant prostate cancer (CRPC), which is associated with a high mortality rate. Generally, well-differentiated PCa cells are androgen dependent, i.e., androgen receptor (AR) signalling regulates cell cycle and differentiation. The loss of AR signalling after ADT triggers androgen-independent outgrowth, generating poorly differentiated, uncontrollable PCa cells. Once PCa cells lose their sensitivity to ADT, effective therapies are limited. In the last few years, however, several new options for the treatment of CRPC have been approved, e.g., the CYP17 inhibitor, the AR antagonist, and the taxane. Despite this progress in the development of new drugs, there is a high medical need for optimizing the sequence and combination of approved drugs. Thus, the identification of predictive biomarkers may help in the context of personalized medicine to guide treatment decisions, improve clinical outcomes, and prevent unnecessary side effects. In this Special Issue Book, we focused on the cytobiology of human PCa cells and its clinical applications to develop a major step towards personalized medicine matched to the individual needs of patients with early-stage and advanced PCa and CRPC. We hope that this Special Issue Book attracts the attention of readers with expertise and interest in the cytobiology of PCa cells.

androgen receptor --- docetaxel --- cabazitaxel --- castration-resistant prostate cancer --- chemotherapy --- P-glycoprotein --- EPI-002 --- splice variant --- prostate-specific antigen --- androgen deprivation therapy --- time to PSA nadir --- fibroblasts --- prostate cancer --- androgen sensitivity --- pirfenidone --- TGFβ1 --- G1 cell cycle arrest --- fibroblast growth factor --- fibroblast growth factor receptor --- obesity --- inflammation --- immune cells --- cytokine --- high-fat diet --- KIFC1 --- docetaxel resistance --- apoptosis --- CW069 --- Caveolin-1 --- TP53-regulated inhibitor of apoptosis 1 --- tumour stroma --- tumour microenvironment --- fibroblast --- CAF --- resistance --- radiotherapy --- CCL2 --- CCL22 --- CCL5 --- migration --- LSD1 --- epigenetics --- autophagy --- abiraterone --- enzalutamide --- testosterone --- castration resistant prostate cancer --- animal model --- diet --- fat --- in vitro --- in vivo --- mouse --- AKR1C3 --- hormone-naïve prostate cancer --- immunohistochemistry --- tissue microarray --- androgen receptor dependency --- fibroblast-dependent androgen receptor activation --- n/a --- hormone-naïve prostate cancer