Régulation des systèmes d'adhérence cellulaire par le CRF2 (un effecteur du stress dans le tube digestif)

Le stress est impliqué dans le développement et l'exacerbation de diverses pathologies notamment au niveau intestinal. Les effets du stress dépendent de l'expression de neuromédiateurs spécifiques (CRF) et de leurs récepteurs. Notre étude porte sur la régulation et la fonction du CRF2 au niveau des entérocytes et des cellules tumorales coliques humaines. In vivo, nous avons montré que le stress et l'inflammation conduisent à l'augmentation de l'expression du CRF2 dans les colonocytes chez le rat. Dans les tumeurs, l'expression du CRF2 augmente avec le grade tumoral. In vitro, dans les cellules HT-29, l'activation du CRF2 induit une altération des jonctions adhérentes et des adhérences focales par la voie Src/ERK/FAK. Ces mécanismes sont responsables de la régulation de la perméabilité épithéliale et de l'augmentation de la migration des cellules tumorales. Ces travaux contribuent à la compréhension des mécanismes impliquant le stress dans le développement des pathologies intestinales.Stress is involved in the initiation and the exacerbation of several diseases especially in the intestine. Stress effects depends on the expression of specific neuromediators (CRF) and there receptors. Our study is about regulation and function of the CRF2, a stress receptor expressed in human enterocytes and colorectal cancer cells. In vivo, we showed that stress and inflammation are responsible for the increased expression of the CRF2 in colon epithelial cells of rats. In tumors, the CRF2 expression is increased with the tumor. In vitro, in HT-29 cells, the CRF2 activation leads to the alteration of adherens junctions and focal adhesions by a Src/ERK/FAK pathway. These mechanisms are responsible for the regulation of epithelial cell permeability and the increased migration of tumor cells. This work contributes to the understanding of the pathways involved in the regulation of intestinal diseases by stress.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1

Funder: Studienstiftung des Deutschen Volkes (German National Academic Foundation); doi: https://doi.org/10.13039/501100004350Funder: Heinrich F.C. Behr StiftungFunder: Dietmar Hopp Stiftung; doi: https://doi.org/10.13039/501100005941Abstract: Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal

Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1

Funder: Studienstiftung des Deutschen Volkes (German National Academic Foundation); doi: https://doi.org/10.13039/501100004350Funder: Heinrich F.C. Behr StiftungFunder: Dietmar Hopp Stiftung; doi: https://doi.org/10.13039/501100005941Abstract: Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal

Regulation of cell adhesion by CRF2 : A stress effector in the digestive tract

Le stress est impliqué dans le développement et l'exacerbation de diverses pathologies notamment au niveau intestinal. Les effets du stress dépendent de l'expression de neuromédiateurs spécifiques (CRF) et de leurs récepteurs. Notre étude porte sur la régulation et la fonction du CRF2 au niveau des entérocytes et des cellules tumorales coliques humaines. In vivo, nous avons montré que le stress et l'inflammation conduisent à l'augmentation de l'expression du CRF2 dans les colonocytes chez le rat. Dans les tumeurs, l'expression du CRF2 augmente avec le grade tumoral. In vitro, dans les cellules HT-29, l'activation du CRF2 induit une altération des jonctions adhérentes et des adhérences focales par la voie Src/ERK/FAK. Ces mécanismes sont responsables de la régulation de la perméabilité épithéliale et de l'augmentation de la migration des cellules tumorales. Ces travaux contribuent à la compréhension des mécanismes impliquant le stress dans le développement des pathologies intestinales.Stress is involved in the initiation and the exacerbation of several diseases especially in the intestine. Stress effects depends on the expression of specific neuromediators (CRF) and there receptors. Our study is about regulation and function of the CRF2, a stress receptor expressed in human enterocytes and colorectal cancer cells. In vivo, we showed that stress and inflammation are responsible for the increased expression of the CRF2 in colon epithelial cells of rats. In tumors, the CRF2 expression is increased with the tumor. In vitro, in HT-29 cells, the CRF2 activation leads to the alteration of adherens junctions and focal adhesions by a Src/ERK/FAK pathway. These mechanisms are responsible for the regulation of epithelial cell permeability and the increased migration of tumor cells. This work contributes to the understanding of the pathways involved in the regulation of intestinal diseases by stress

Régulation des systèmes d'adhérence cellulaire par le CRF2 : un effecteur du stress dans le tube digestif

Stress is involved in the initiation and the exacerbation of several diseases especially in the intestine. Stress effects depends on the expression of specific neuromediators (CRF) and there receptors. Our study is about regulation and function of the CRF2, a stress receptor expressed in human enterocytes and colorectal cancer cells. In vivo, we showed that stress and inflammation are responsible for the increased expression of the CRF2 in colon epithelial cells of rats. In tumors, the CRF2 expression is increased with the tumor. In vitro, in HT-29 cells, the CRF2 activation leads to the alteration of adherens junctions and focal adhesions by a Src/ERK/FAK pathway. These mechanisms are responsible for the regulation of epithelial cell permeability and the increased migration of tumor cells. This work contributes to the understanding of the pathways involved in the regulation of intestinal diseases by stress.Le stress est impliqué dans le développement et l'exacerbation de diverses pathologies notamment au niveau intestinal. Les effets du stress dépendent de l'expression de neuromédiateurs spécifiques (CRF) et de leurs récepteurs. Notre étude porte sur la régulation et la fonction du CRF2 au niveau des entérocytes et des cellules tumorales coliques humaines. In vivo, nous avons montré que le stress et l'inflammation conduisent à l'augmentation de l'expression du CRF2 dans les colonocytes chez le rat. Dans les tumeurs, l'expression du CRF2 augmente avec le grade tumoral. In vitro, dans les cellules HT-29, l'activation du CRF2 induit une altération des jonctions adhérentes et des adhérences focales par la voie Src/ERK/FAK. Ces mécanismes sont responsables de la régulation de la perméabilité épithéliale et de l'augmentation de la migration des cellules tumorales. Ces travaux contribuent à la compréhension des mécanismes impliquant le stress dans le développement des pathologies intestinales

Stress neuromediators are key regulators of the intestinal barrier: Link to inflammation and cancer: Stress neuromediators regulate the intestinal barrier

ReviewInternational audienceIn the past year, the influence of psychosocial and environmental stressors in different pathogenesis received increased awareness. The brain is the master manager of the interpretation of what is stressful and of the physiological responses that are produced. Animals have developed conserved strategies to respond to stressful conditions, in particular, the secretion of stress-specific neuromediators which mediate protective and adaptative effects in the short run and yet can accelerate pathophysiology when they are over-produced or mis-managed. The Cortico-Releasing Factor (CRF) and their derived peptides are the majors stress neuromediators. Their localization has originally been described in the central nervous system where they play a pivotal role to activate the hypothalamic-pituitary-adrenal (HPA) axis and was recently extended to the periphery. While the peripheral effects of CRF signalling need to be more thoroughly investigated, it has been described to influence disease negatively, in particular in the intestine. The epithelial barrier is a crucial checkpoint to control body entrances. Prolonged exposure to stress can cause ultrastructural epithelial abnormalities and can increase barrier permeability, which favors luminal translocation, immune activation and thus induces inflammation. This review summarizes the present knowledge on the stress response and the effects of both acute and chronic stress to induce pathological damage to the intestine. We present the potential pathways involved, and the proposed mechanisms of action, mediating these effects. The CRF system is potentially useful as a diagnostic marker or a therapy target for inflammatory diseases and cancer

Role of cholinergic receptors in colorectal cancer: potential therapeutic implications of vagus nerve stimulation?

International audiencelapsing intestinal inflammation that favours the development of colitis associated cancer (CAC). This inflammation is initiated by aberrant activations of the innate immune responses associated to intestinal barrier defects. The conven-tional medical therapies consist to decrease the inflammatory response, which also decrease the risk of colon carcinoma but lead to severe side-effects. Recently, a number of animal studies have demonstrated that innate immune responses are attenuated by stimulation of the efferent arm of vagus nerve (VN) through its neurotransmitter acetylcholine (ACh), that acts on resident macrophages α7 nicotinic receptor (α7 nAChR). ACh also acts as a signalling molecule in epithet- lial cells through cholinergic receptors such as nAChR or muscarinic (mAChR) receptors. In the current study, we aimed to extend these findings to CAC prevention by treating human adenocarcinoma cell lines through targeting cho- linergic receptors with nicotine (which binds nAChR) and ACh (which binds both cholinergic receptors). Using HT-29 and Caco-2 cell lines, we demonstrated that ACh-induced activation of mAChR results in cell dissociation together with changes in expression and localization of intestinal tight and adherens junction proteins. ACh-induced modulation of cell adhesion proprieties correlates with the acquisition of invasive potential. By contrast, nicotine-mediated activation of nAChR maintains epithelial cell organisation. ACh-released by VN stimulation (VNS) could effectively preserve epithelium integrity thus limiting inflammatory response and tumor development. However, attention should be paid on the nature of the cholinergic receptor solicited. Indeed, regarding to the protective effects of nAChR signalling on epithelial cells, activation of mAChR would worsen the disease and led to increase inflammation. These data have im- portant repercussions on the therapeutic potential of VNS in IBD and CAC, which may represent "the yin and yang" of the intestinal homeostasis

Cyclin-dependent kinase 2/cyclin E complex is involved in p120 catenin (p120ctn)-dependent cell growth control: a new role for p120ctn in cancer.

International audienceDepending on its cellular localization, p120 catenin (p120ctn) can participate in various processes, such as cadherin-dependent cell-cell adhesion, actin cytoskeleton remodeling, and intracellular trafficking. Recent studies also indicate that p120ctn could regulate cell proliferation and contact inhibition. This report describes a new function of p120ctn in the regulation of cell cycle progression. Overexpression of the p120ctn isoform 3A in human colon adenocarcinoma cells (HT-29) results in cytoplasmic accumulation of the protein, as observed in many tumors. This cytoplasmic increase is correlated with a reduction in proliferation and inhibition of DNA synthesis. Under these conditions, experiments on synchronized cells revealed a prolonged S phase associated with cyclin E stabilization. Both confocal microscopy and biochemical analysis showed that cyclin E and cyclin-dependent kinase 2 colocalized with p120ctn in centrosomes during mitosis. These proteins are associated in a functional complex evidenced by coimmunoprecipitation experiments and the emergence of Thr199-phosphorylated nucleophosmin/B23. Such post-translational modification of this centrosomal target has been shown to trigger the initiation of centrosome duplication. Therefore, p120ctn-mediated accumulation of cyclin E in centrosomes may participate in abnormal amplification of centrosomes and the inhibition of DNA replication, thus leading to aberrant mitosis and polyploidy. Because these modifications are often observed in cancer, p120ctn may represent a new therapeutic target for future therapy