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Expression des pompes calcique de type SERCA dans l’épithélium du plexus choroïde normal et tumoral et au cours de la différenciation précoce des lymphocytes B

Abstract : Cellular calcium is involved in a multitude of biological processes including thecontrol of cell proliferation, differentiation and programmed cell death, and constitutestherefore a keconcentration calcique cytosolique de calcium subit des oscillations, qui suivant leuramplitude ou leur fréquence, vont être capables d’activer spécifiquement certains facteursde transcription. La régulation de ces oscillations implique entre autres les ATPases de typeSERCA (Sarco/Endoplasmic Reticulum Calcium ATPase) qui accumulent le calcium dansle réticulum endoplasmique. L’objectif de ce travail de thèse a été l’étude des SERCAs aucours de la différenciation lymphocytaire B et dans l’épithélium du plexus choroïde ; ceci,afin de mieux comprendre le profil d’expression de ces pompes et les mécanismes derégulation impliqués.Au cours de la différenciation de lignées de leucémie aiguë lymphoblastique (LAL) nousavons observé que l’expression de l’isoforme SERCA2 restait stable ou augmentaitlégèrement alors que celle de l’isoforme SERCA3 était toujours fortement induite, pouvantatteindre des niveaux observés dans les cellules lymphoïdes matures. Nous avons égalementobservé que l’inhibition de l’activité des SERCAs altère la différenciation cellulaire qui estdépendante de la voie des PKC. Ces données indiquent que SERCA3 pourrait être utiliséey element in cell signaling. Calcium levels vary in a dynamic mannerdepending on the state of activation of the cell, and can display oscillations the amplitudeand frequency of which can convey specific signals to various transcription factors.Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes) accumulate calciumfrom the cytosol into the endoplasmic reticulum (ER). By modulating the spatiotemporalcharacteristics of calcium signals and oscillations, SERCA pumps constitute an importantand unique point of control of calcium-dependent cell activation. In this work weinvestigated SERCA expression during early B lymphoid differentiation and in normal,tumoral and hyperplastic choroid plexus epithelial cells.We have shown that SERCA3 expression is markedly increased during thepharmacologically induced differentiation of immature B acute lymphoblastic leukemiacells, whereas the expression of the simultaneously expressed SERCA2 isoform is notmodified significantly. SERCA3 expression during this differentiation process can reachlevels observed in mature B lymphoid cells, and is dependent on the activation of proteinkinase C. Moreover, the direct pharmacological inhibition of SERCA-dependent calciumtransport interferes with the differentiation process.Our investigations on the choroid plexus show, that whereas SERCA3 is highly expressedin normal choroid plexus epithelium, expression is strongly decreased in benign choroidplexus tumors and is lost in carcinoma, whereas expression is retained in hyperplasia. Inaddition, treatment of primary normal choroid plexus epithelial cells by short chain fattyacid-type cell differentiation-inducing agents in vitro leads to the induction of SERCA3expression.Our observations when taken together indicate that ER calcium homeostasis is remodeledduring the differentiation of immature B lymphoid cells and in the choroid plexus due to theinduction of SERCA3 expression. We show that a cross-talk exists between SERCA functionand the control of differentiation in B cells, that SERCA3 constitutes a new phenotypicmarker for the study of early B cell differentiation, and that the lack of SERCA3 expressionmay be useful for the identification of choroid plexus tumors.
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Lamia Ait Ghezali. Expression des pompes calcique de type SERCA dans l’épithélium du plexus choroïde normal et tumoral et au cours de la différenciation précoce des lymphocytes B. Autre [q-bio.OT]. Université Sorbonne Paris Cité, 2017. Français. ⟨NNT : 2017USPCD015⟩. ⟨tel-01874231⟩

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