Biomarkers of human gastrointestinal tract regions.

Dysregulation of intestinal epithelial cell performance is associated with an array of pathologies whose onset mechanisms are incompletely understood. While whole-genomics approaches have been valuable for studying the molecular basis of several intestinal diseases, a thorough analysis of gene expression along the healthy gastrointestinal tract is still lacking. The aim of this study was to map gene expression in gastrointestinal regions of healthy human adults and to implement a procedure for microarray data analysis that would allow its use as a reference when screening for pathological deviations. We analyzed the gene expression signature of antrum, duodenum, jejunum, ileum, and transverse colon biopsies using a biostatistical method based on a multivariate and univariate approach to identify region-selective genes. One hundred sixty-six genes were found responsible for distinguishing the five regions considered. Nineteen had never been described in the GI tract, including a semaphorin probably implicated in pathogen invasion and six novel genes. Moreover, by crossing these genes with those retrieved from an existing data set of gene expression in the intestine of ulcerative colitis and Crohn's disease patients, we identified genes that might be biomarkers of Crohn's and/or ulcerative colitis in ileum and/or colon. These include CLCA4 and SLC26A2, both implicated in ion transport. This study furnishes the first map of gene expression along the healthy human gastrointestinal tract. Furthermore, the approach implemented here, and validated by retrieving known gene profiles, allowed the identification of promising new leads in both healthy and disease states.

The Role of Secretory Immunoglobulin A in the Natural Sensing of Commensal Bacteria by Mouse Peyer's Patch Dendritic Cells.

The mammalian gastrointestinal (GI) tract harbors a diverse population of commensal species collectively known as the microbiota, which interact continuously with the host. From very early in life, secretory IgA (SIgA) is found in association with intestinal bacteria. It is considered that this helps to ensure self-limiting growth of the microbiota and hence participates in symbiosis. However, the importance of this association in contributing to the mechanisms ensuring natural host-microorganism communication is in need of further investigation. In the present work, we examined the possible role of SIgA in the transport of commensal bacteria across the GI epithelium. Using an intestinal loop mouse model and fluorescently labeled bacteria, we found that entry of commensal bacteria in Peyer's patches (PP) via the M cell pathway was mediated by their association with SIgA. Preassociation of bacteria with nonspecific SIgA increased their dynamics of entry and restored the reduced transport observed in germ-free mice known to have a marked reduction in intestinal SIgA production. Selective SIgA-mediated targeting of bacteria is restricted to the tolerogenic CD11c(+)CD11b(+)CD8(-) dendritic cell subset located in the subepithelial dome region of PPs, confirming that the host is not ignorant of its resident commensals. In conclusion, our work supports the concept that SIgA-mediated monitoring of commensal bacteria targeting dendritic cells in the subepithelial dome region of PPs represents a mechanism whereby the host mucosal immune system controls the continuous dialogue between the host and commensal bacteria.

2

The pharmacokinetic profile of imatinib has been assessed in healthy subjects and in population studies among thousands of patients with CML or GIST. Imatinib is rapidly and extensively absorbed from the GI tract, reaching a peak plasma concentration (Cmax) within 1-4 h following administration. Imatinib bioavailability is high (98%) and independent of food intake. Imatinib undergoes rapid and extensive distribution into tissues, with minimal penetration into the central nervous system. In the circulation, it is approximately 95% bound to plasma proteins, principally α1-acid glycoprotein (AGP) and albumin. Imatinib undergoes metabolism in the liver via the cytochrome P450 enzyme system (CYP), with CYP3A4 being the main isoenzyme involved. The N-desmethyl metabolite CGP74588 is the major circulating active metabolite. The typical elimination half-life for imatinib is approximately 14-22 h. Imatinib is characterized by large inter-individual pharmacokinetic variability, which reflects in a wide spread of concentrations observed under standard dosage. Besides adherence, several factors have been shown to influence this variability, especially demographic characteristics (sex, age, body weight and disease diagnosis), blood count characteristics, enzyme activity (mainly CYP3A4), drug interactions, activity of efflux transporters and plasma levels of AGP. Additionally, recent retrospective studies have shown that drug exposure, reflected in either the area under the concentration-time curve (AUC) or more conveniently the trough level (Cmin), correlates with treatment outcomes. Increased toxicity has been associated with high plasma levels, and impaired clinical efficacy with low plasma levels. While no upper concentration limit has been formally established, a lower limit for imatinib Cmin of about 1000 ng/mL has been proposed repeatedly for improving outcomes in CML and GIST patients. Imatinib is licensed for use in chronic phase CML and GIST at a fixed dose of 400 mg once daily (600 mg in some other indications) despite substantial pharmacokinetic variability caused by both genetic and acquired factors. The dose can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Imatinib would, however, meet traditional criteria for a therapeutic drug monitoring (TDM) program: long-term therapy, measurability, high inter-individual but restricted intra-individual variability, limited pharmacokinetic predictability, effect of drug interactions, consistent association between concentration and response, suggested therapeutic threshold, reversibility of effect and absence of early markers of efficacy and toxic effects. Large-scale, evidence-based assessments of drug concentration monitoring are therefore still warranted for the personalization of imatinib treatment.

Acute norovirus-induced agranulocytosis in a pediatric kidney transplant recipient.

Norovirus (NoV) infection is usually limited to the gastrointestinal (GI) tract. However, in immunocompromised patients, this infection might lead to severe life-threatening complications. We herein describe a pediatric kidney transplant patient who presented with an acute NoV infection complicated by febrile agranulocytosis that resolved with improvement of her GI illness. This unusual presentation has not been described before, to our knowledge. The aim of this article is to highlight the sometimes dramatic clinical presentation of NoV infection in immunosuppressed patients, and the importance of including this infection in the differential diagnosis of neutropenia in that specific population.

Candida albicans Inhibits Pseudomonas aeruginosa Virulence through Suppression of Pyochelin and Pyoverdine Biosynthesis.

Bacterial-fungal interactions have important physiologic and medical ramifications, but the mechanisms of these interactions are poorly understood. The gut is host to trillions of microorganisms, and bacterial-fungal interactions are likely to be important. Using a neutropenic mouse model of microbial gastrointestinal colonization and dissemination, we show that the fungus Candida albicans inhibits the virulence of the bacterium Pseudomonas aeruginosa by inhibiting P. aeruginosa pyochelin and pyoverdine gene expression, which plays a critical role in iron acquisition and virulence. Accordingly, deletion of both P. aeruginosa pyochelin and pyoverdine genes attenuates P. aeruginosa virulence. Heat-killed C. albicans has no effect on P. aeruginosa, whereas C. albicans secreted proteins directly suppress P. aeruginosa pyoverdine and pyochelin expression and inhibit P. aeruginosa virulence in mice. Interestingly, suppression or deletion of pyochelin and pyoverdine genes has no effect on P. aeruginosa's ability to colonize the GI tract but does decrease P. aeruginosa's cytotoxic effect on cultured colonocytes. Finally, oral iron supplementation restores P. aeruginosa virulence in P. aeruginosa and C. albicans colonized mice. Together, our findings provide insight into how a bacterial-fungal interaction can modulate bacterial virulence in the intestine. Previously described bacterial-fungal antagonistic interactions have focused on growth inhibition or colonization inhibition/modulation, yet here we describe a novel observation of fungal-inhibition of bacterial effectors critical for virulence but not important for colonization. These findings validate the use of a mammalian model system to explore the complexities of polymicrobial, polykingdom infections in order to identify new therapeutic targets for preventing microbial disease.

Disease-causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE-2 and antisense Alu lacking the poly(T)-tail.

Cryptic exons or pseudoexons are typically activated by point mutations that create GT or AG dinucleotides of new 5' or 3' splice sites in introns, often in repetitive elements. Here we describe two cases of tetrahydrobiopterin deficiency caused by mutations improving the branch point sequence and polypyrimidine tracts of repeat-containing pseudoexons in the PTS gene. In the first case, we demonstrate a novel pathway of antisense Alu exonization, resulting from an intronic deletion that removed the poly(T)-tail of antisense AluSq. The deletion brought a favorable branch point sequence within proximity of the pseudoexon 3' splice site and removed an upstream AG dinucleotide required for the 3' splice site repression on normal alleles. New Alu exons can thus arise in the absence of poly(T)-tails that facilitated inclusion of most transposed elements in mRNAs by serving as polypyrimidine tracts, highlighting extraordinary flexibility of Alu repeats in shaping intron-exon structure. In the other case, a PTS pseudoexon was activated by an A>T substitution 9 nt upstream of its 3' splice site in a LINE-2 sequence, providing the first example of a disease-causing exonization of the most ancient interspersed repeat. These observations expand the spectrum of mutational mechanisms that introduce repetitive sequences in mature transcripts and illustrate the importance of intronic mutations in alternative splicing and phenotypic variability of hereditary disorders.

In vitro growth of human urinary tract smooth muscle cells on laminin and collagen type I-coated membranes under static and dynamic conditions.

This study investigates in vitro growth of human urinary tract smooth muscle cells under static conditions and mechanical stimulation. The cells were cultured on collagen type I- and laminin-coated silicon membranes. Using a Flexcell device for mechanical stimulation, a cyclic strain of 0-20% was applied in a strain-stress-time model (stretch, 104 min relaxation, 15 s), imitating physiological bladder filling and voiding. Cell proliferation and alpha-actin, calponin, and caldesmon phenotype marker expression were analyzed. Nonstretched cells showed significant better growth on laminin during the first 8 days, thereafter becoming comparable to cells grown on collagen type I. Cyclic strain significantly reduced cell growth on both surfaces; however, better growth was observed on laminin. Neither the type of surface nor mechanical stimulation influenced the expression pattern of phenotype markers; alpha-actin was predominantly expressed. Coating with the extracellular matrix protein laminin improved in vitro growth of human urinary tract smooth muscle cells.

Is the diagnostic yield of upper GI endoscopy improved by the use of explicit panel-based appropriateness criteria?

BACKGROUND: Increasing the appropriateness of use of upper gastrointestinal (GI) endoscopy is important to improve quality of care while at the same time containing costs. This study explored whether detailed explicit appropriateness criteria significantly improve the diagnostic yield of upper GI endoscopy. METHODS: Consecutive patients referred for upper GI endoscopy at 6 centers (1 university hospital, 2 district hospitals, 3 gastroenterology practices) were prospectively included over a 6-month period. After controlling for disease presentation and patient characteristics, the relationship between the appropriateness of upper GI endoscopy, as assessed by explicit Swiss criteria developed by the RAND/UCLA panel method, and the presence of relevant endoscopic lesions was analyzed. RESULTS: A total of 2088 patients (60% outpatients, 57% men) were included. Analysis was restricted to the 1681 patients referred for diagnostic upper GI endoscopy. Forty-six percent of upper GI endoscopies were judged to be appropriate, 15% uncertain, and 39% inappropriate by the explicit criteria. No cancer was found in upper GI endoscopies judged to be inappropriate. Upper GI endoscopies judged appropriate or uncertain yielded significantly more relevant lesions (60%) than did those judged to be inappropriate (37%; odds ratio 2.6: 95% CI [2.2, 3.2]). In multivariate analyses, the diagnostic yield of upper GI endoscopy was significantly influenced by appropriateness, patient gender and age, treatment setting, and symptoms. CONCLUSIONS: Upper GI endoscopies performed for appropriate indications resulted in detecting significantly more clinically relevant lesions than did those performed for inappropriate indications. In addition, no upper GI endoscopy that resulted in a diagnosis of cancer was judged to be inappropriate. The use of such criteria improves patient selection for upper GI endoscopy and can thus contribute to efforts aimed at enhancing the quality and efficiency of care. (Gastrointest Endosc 2000;52:333-41).

Microbiological diagnosis of community-acquired respiratory tract infections by nucleic acid detection.

Background: Microbiological diagnostic procedures have changed significantly over the last decade. Initially the implementation of the polymerase chain reaction (PCR) resulted in improved detection tests for microbes that were difficult or even impossible to detect by conventional methods such as culture and serology, especially in community-acquired respiratory tract infections (CA-RTI). A further improvement was the development of real-time PCR, which allows end point detection and quantification, and many diagnostic laboratories have now implemented this powerful method. Objective: At present, new performant and convenient molecular tests have emerged targeting in parallel many viruses and bacteria responsible for lower and/or upper respiratory tract infections. The range of test formats and microbial agents detected is evolving very quickly and the added value of these new tests needs to be studied in terms of better use of antibiotics, better patient management, duration of hospitalization and overall costs. Conclusions: Molecular tools for a better microbial documentation of CA-RTI are now available. Controlled studies are now required to address the relevance issue of these new methods, such as, for example, the role of some newly detected respiratory viruses or of the microbial DNA load in a particular patient at a particular time. The future challenge for molecular diagnosis will be to become easy to handle, highly efficient and cost-effective, delivering rapid results with a direct impact on clinical management.

Coffee consumption and digestive tract cancers.

The relationship between coffee drinking and the risk of digestive tract neoplasms was analyzed in a case-control study of 50 cases of cancer of the mouth or pharynx, 209 of the esophagus, 397 of the stomach, 455 of the colon, 295 of the rectum, 151 of the liver, 214 of the pancreas, and 1944 control subjects admitted for acute, non-digestive tract disorders. There was no significant or consistent association between coffee and cancers of the mouth or pharynx, esophagus, stomach, liver, or pancreas. In particular, for pancreatic cancer, the multivariate relative risks for the intermediate and upper tertiles were 1.05 and 1.01, respectively. There were significant inverse trends in risk with measures of coffee consumption for colon and rectal cancers, the multivariate relative risks according to tertiles of coffee consumption being 0.86 and 0.64 for colon and 0.97 and 0.66 for rectum. This apparent protection is in agreement with some (but not all) previous epidemiological evidence and finds a possible biological interpretation in terms of interference on bile secretion, causing reduced bile acid and neutral sterol concentrations in the bowel. In conclusion, the results of this study, the major interest of which lies in the opportunity of drawing up an overall pattern of risk for various digestive neoplasms, offer further reassurance as regards the effects of coffee on digestive tract carcinogenesis.

Reduction of the hand representation in the ipsilateral primary motor cortex following unilateral section of the corticospinal tract at cervical level in monkeys.

BACKGROUND: After sub-total hemi-section of cervical cord at level C7/C8 in monkeys, the ipsilesional hand exhibited a paralysis for a couple of weeks, followed by incomplete recovery of manual dexterity, reaching a plateau after 40-50 days. Recently, we demonstrated that the level of the plateau was related to the size of the lesion and that progressive plastic changes of the motor map in the contralesional motor cortex, particularly the hand representation, took place following a comparable time course. The goal of the present study was to assess, in three macaque monkeys, whether the hand representation in the ipsilesional primary motor cortex (M1) was also affected by the cervical hemi-section.¦RESULTS: Unexpectedly, based on the minor contribution of the ipsilesional hemisphere to the transected corticospinal (CS) tract, a considerable reduction of the hand representation was also observed in the ipsilesional M1. Mapping control experiments ruled out the possibility that changes of motor maps are due to variability of the intracortical microstimulation mapping technique. The extent of the size reduction of the hand area was nearly as large as in the contralesional hemisphere in two of the three monkeys. In the third monkey, it represented a reduction by a factor of half the change observed in the contralesional hemisphere. Although the hand representation was modified in the ipsilesional hemisphere, such changes were not correlated with a contribution of this hemisphere to the incomplete recovery of the manual dexterity for the hand affected by the lesion, as demonstrated by reversible inactivation experiments (in contrast to the contralesional hemisphere). Moreover, despite the size reduction of M1 hand area in the ipsilesional hemisphere, no deficit of manual dexterity for the hand opposite to the cervical hemi-section was detected.¦CONCLUSION: After cervical hemi-section, the ipsilesional motor cortex exhibited substantial reduction of the hand representation, whose extent did not match the small number of axotomized CS neurons. We hypothesized that the paradoxical reduction of hand representation in the ipsilesional hemisphere is secondary to the changes taking place in the contralesional hemisphere, possibly corresponding to postural adjustments and/or re-establishing a balance between the two hemispheres.

Function and regulation of the scaffold protein IB1/JIP-1 in the uro-genital tract.

RESUME Ce mémoire de thèse traite de l'étude de la « scaffold »protéine ou protéine «échafaud», « Islet-Brain1/ JNK Interacting Protein 1 » (IB1/JIP-1) dans la vessie et la prostate, deux organes importants de l'appareil uro-genital. Cette protéine, mise en évidence dans notre laboratoire à la fin des année 90, a été reconnue pour réguler la voie de signalisation des « Mitogen-Activated Protein Kinases » (MAPKs), et en particulier de la MAPK appelée c-Jun N-terminal Kinase (JNK). Le réseau de voie de signalisation permet aux cellules de percevoir les changements dans le milieu extracellulaire et de permettre une réponse appropriée à ces différents stimuli. La connaissance des voies de signalisation a permis de mettre en évidence leur rôle crucial tant dans l'homéostase des tissus sains que dans des processus pathologiques comme l'oncogenèse. Parmi une vingtaine de voie de signalisation, la voie de signalisation des «MAPKinases » est une des plus importantes et a été montrée pour participer à diverses fonctions cellulaires telles que la différentiation, la motilité, la division et la mort cellulaire. La voie de signalisation des « MAPKinases » est typiquement constituée d'un module de trois kinases qui s'activent séquentiellement par phosphorylation. On note la présence d'une MAPK, d'un activateur de MAPK et d'un activateur de l'activateur de MAPK. Une fois la MAPK activée, elle permettra la régulation de différentes cibles dont certain facteur de transcription. Chez les mammifères, il existe 3 grands groupes de MAPKs : the extracellular signal-regulated kinase 1 and 2 (ERK 1/2) cascade, qui régule préférentiellement la croissance et la différentiation cellulaire, ainsi que les cascades JNK et p38 qui régulent préférentiellement la réponse à différents stress cellulaires telle que l'inflammation ou l'apoptose. JNK est activé par différents stress cellulaire telle que les cytokines inflammatoires. JNK est également requis au cours du développement embryonnaire et contribue à la mort (apoptose) ou à la prolifération cellulaire. Plusieurs études ont mis en évidence le rôle de JNK durant le processus tumoral, sans que son rôle soit clairement identifié. JNK pourrait avoir des fonctions différentes durant l'initiation puis de la progression tumorale. Chez les mammifères, les voies de signalisation intracellulaires forment un réseau complexe et elles interagissent entre elles, ce qui permet aux cellules une réponse adéquate aux multitudes de stimuli existants dans les organismes pluricellulaires. Parmi plusieurs mécanismes de régulation, les protéines dites « scaffold » ou «échafaud » jouent un rôle crucial dans l'homéostase de la voie de signalisation des «MAPKinase ». L'introduction revoit brièvement ces différents aspects, de la voie de signalisation des «MAPKinase et des connaissance sur IB1/JIP-1. Les premières études effectuées sur IB1/JIP-1 ont montré une expression relativement spécifique de cette protéine dans certains types de neurones ainsi que dans la cellule beta-sécrétrice d'insuline. IB1/JIP-1 régule la voie de signalisation JNK par interaction avec les différents composants du module, modifiant ainsi le spectre de substrats activés par JNK. La fonction précise de IB1/JIP-1 n'était pas encore élucidée, mais plusieurs travaux mettaient en lumière un rôle dans la régulation, et la sous-location cellulaire des composants de la voie de signalisation JNK, ainsi que dans la survie cellulaire à certain stress. Cette expression relativement spécifique est intrigante car elle suggère que sa présence serait nécessaire à une régulation spécifique de la MAPKinase JNK ou à certaines autres fonctions cellulaires également spécifiques de certains tissus. Le premier but de ce travail a consisté à mettre en évidence l'expression de IB1/JIP-1 dans l'appareil uro-génital et plus particulièrement dans la vessie et la prostate. Nos résultats ont montré que IB1/JIP-1 est spécifiquement exprimé au niveau de l'urothélium vésical, mais pas dans le muscle lisse. Il en est de même au niveau de la prostate où IB1/JIP-1 est exprimé spécifiquement au niveau de l'épithélium sécrétoire et absent au niveau du stroma fibro-musculaire. La vessie et la prostate sont des organes ou l'activité JNK pourrait être crucial tant dans l' homeostase tissulaire que dans le développement de pathologies bénignes ou malignes. La vessie et la prostate sont le siège fréquent de tumeur. La base pour le développement du cancer est complexe et implique plusieurs anomalies génétiques. Ce processus complexe lié au développement tumoral est encore loin d`être complètement élucidé, raison pour laquelle il est crucial de poursuivre l'étude des différents gènes pouvant être impliqué dans ces processus ou pouvant être utilisé comme outil thérapeutique. Dans l'urothelium de la vessie, la fonction de la MAPK JNK n'a été que très peu étudiée. Il existe quelques études, in vitro, suggérant une implication possible de cette voie de signalisation dans des processus telle que le développement ou la progression tumorale. Le chapitre 1 décrit une étude in vivo dans la vessie un modèle de stress mécanique, connu pour activer les MAPKinase. La dilatation vésicale, due à une obstruction urétrale, a mis en évidence une diminution de l'expression de IB1/JIP-1 ainsi qu'une activation de la MAPKinase JNK. Dans ce modèle, la régulation de IB1/JIP-1, par l'intermédiaire d'un vecteur viral, a permis de démontrer que IB1/JIP-1 régulait l'activité de JNK dans ce tissu. Pour poursuivre l'étude de cette fonction d' IB1/JIP-1 dans l'urothélium, nous avons investigué l'activité JNK dans des souris génétiquement modifiées et porteuse d'une délétion de 1 des 2 allèles du gène codant pour IB1/JIP-1, avec un contenu en IB1/JIP-1 diminué de moitié. L'activation de JNK est également augmentée dans l'urothelium au repos de ces souris, ce qui confirme la fonction régulatrice de JNK par IB1/JIP-1. Ces résultats ont permis de mettre en évidence un rôle critique de celle-ci dans l'homéostase de I`urothelium et suggère une nouvelle cible pour réguler la voie de signalisation dans ce tissu. En outre, la modulation des niveaux d'expression d'IB1/JIP-1 dans la vessie, in vivo, par l'intermédiaire de vecteurs viraux s'est révélée réalisable et indique un moyen élégant pour développer une thérapie génique dans cet organe. Un autre élément de ce travail de thèse, révélée au chapitre 2, a été d'étudier la régulation dans la vessie de rat de la communication intercellulaire de type « GAP ». Les cellules adjacentes partagent des ions, messagers secondaires et des petits métabolites par l'intermédiaire de canaux intercellulaire qui forment les jonctions de type « GAP ». Ce type de communications intercellulaire permet une activité cellulaire coordonnée, une caractéristique importante pour l'homéostase des organismes multicellulaire. Ce type de communication intercellulaire est formé de 2 demi-canaux appelés connexons. Chaque connexon est formé de six protéines appelées connexins (Cx). Il existe environ vingt connexines différentes nommées par leur poids moléculaire respectif. Les jonctions de type canaux "GAP" permettent aux cellules de communiquer avec les cellules voisines au quelles elles sont mécaniquement ou électriquement couplées. La vessie peut être particulièrement dépendante de la communication intercellulaire par les canaux « Gap » qui permettrait de coordonner la réponse de la musculature ainsi que de l'urothélium à l'augmentation de la pression transmurale du à l'accumulation d'urine, situation fréquemment observée dans le cadre de l'hyperplasie bénigne de la prostate. Dans la vessie de rat, la connexine26 est exprimée uniquement dans l'urothelium. La Cx26, a été montrée pour être un possible « tumor suppressor gene » dans le cancer de vessie. Une augmentation de la Cx26 ainsi que du couplage des cellules urothéliales a été démontré dans notre modèle de stress mécanique sur la vessie de rat et est dépendante de 2 éléments de réponses connues pour interagir avec AP-1. La régulation de IB1/JIP-1 a permis de montrer que celle-ci régulait l'activité JNK, ainsi que l'activité du facteur de transcription AP-1, composé de c-Jun lui-même cible de JNK. Cette réduction de l'activité de AP-1 est associée à une diminution de l'expression du transcipt de la Cx26. En résumé, la Cx26 pourrait être régulée par le complexe AP-1 lui-même dépendant du contenu en IB1/JIP-1. Dans le chapitre 3, l'étude de IB1/J1P-1 s'est portée sur la prostate. Cet organe, siège fréquent de pathologie telle que le cancer ou l'hyperplasie bénigne de la prostate, exprime IB1/JIP-1 au niveau de son épithélium sécrétoire. Cette expression est maintenue dans une lignée cellulaire humaine largement étudiée est reconnue comme un modèle adéquat de cellules tumorales de type androgène-sensible. IB1/JIP-1 a été investigué dans un modèle in vitro d'apoptose en réponse à un agent appelé N-(4-hydroxyphenyl)retinamide (4-HPR) qui induit une activation de la MAPK JNK ainsi que également un diminution du contenu en IB1/JIP-1. La surexpression de IB1/JIP-1 en utilisant à nouveau des virus comme vecteur a démontré que IB1/JIP-1 était capable de réguler l'activité de JNK ainsi que les taux d'apoptose. Dans le cancer de la prostate, certains travaux ont montré que la différentiation neuroendocrine des cellules tumorales est associée à la progression tumorale et à la perte de sensibilité aux androgènes. Ce travail a permis de dévoiler l'augmentation d'expression de IB1/JIP-1 dans un modèle de neurodifferentiation des cellules d'une lignée prostatique humaine (LNCaP). Les mécanismes qui permettent une expression spécifique de IB1/JIP-1 ont été partiellement investiguée dans notre laboratoire. Son promoteur humain contient un « Neuron Restricive Silencer Element » (NRSE) connu pour se lier a répresseur transcriptionel appelé « RE-1 Silencer Transcription Factor » ou « Neuron Restrictive Silencer Factor » (REST/NRSF). NRSF/REST est capable de réprimer l'expression de gènes neuronaux en dehors du système neuronal. Il prend part à la différentiation terminale des gènes neuronaux. Dans le chapitre 3, on observe que l'activité de REST/NRSF est diminuée dans les cellules LNCaP qui se transdifferencient de manière neuroendocrine, et que REST/NRSF est capable de moduler l'expression de ces gènes cibles dans ce type cellulaire. Ces travaux laissent suggérer que NRSF/REST participe à l'acquisition du phénotype neuroendocrinien et pourrait être une cible pour réguler ce phénomène. En conclusion, ce travail de thèse présente l'expression de IB1/JIP-1 dans 2 organes de l'appareil uro-génital ; la vessie et la prostate. La fonction de IB1/JIP-1 a été étudiée in vivo dans la vessie de rat, ce qui a mis en évidence sa fonction régulatrice de l'activité de la MAPKinase JNK, et de l'activité du facteur de transcription AP-1 ; ainsi que sa possible implication régulatrice de gène cible tel que la Connexin 26 (Cx26). AP-1 et la Cx26 pourraient jouer un rôle dans le processus oncologique, tant dans le control de l'invasion cellulaire ou le control de la croissance cellulaire. Dans la prostate, IB1/JIP-1 régule également l'activité JNK; crucial dans la transmission de certains stimulis pro-apoptotiques. Dans un modèle de transdifférenciation neuroendocrinienne, phénotype possiblement lié au caractère agressif du cancer de la prostate, l'expression de IB1/JIP-1 est augmenté, suggérant soit un rôle possible dans le développement du phénotype neuronal ou une implication dans une fonction anti-apoptotique. Ce travail a donc permis d'élargir nos connaissances sur la régulation et le control de la voie de signalisation des MAPKinases par IB1/JIP-1, qui pourrait avoir encore d'autres fonctions dans ces tissus.