1,721,003 research outputs found
Signaling Crosstalks Drive Generation and Regeneration of the Thymus
No full textOptimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting
The mazy case of Notch and immunoregulatory cells
No full textThe Notch pathway represents a conserved signal transduction machinery that is straightforward and based on a few elements (ligands, receptors, transducers). However, the existence of multiple control levels of the Notch signaling final outcome makes it strictly context dependent and dose dependent. The function of Notch as a regulator of cell development and differentiation, as well as the aberrant consequences of its modulation, either positive or negative, is well established. In this review, we will discuss our current knowledge about Notch-dependent regulation of generation and function of 2 subsets of the immunoregulatory system, namely regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Then, we will focus on an unforeseen mechanism that may unveil an additional way of Notch to govern the surrounding environment in cancer
Notch3: from subtle structural differences to functional diversity
No full textThe Notch3 gene was identified, at the beginning of 90s, as the third mammalian Notch and was initially reported as being expressed in proliferating neuroepithelium. Since then, increasing evidence has demonstrated a number of structural and functional differences between Notch3 and both Notch1 and Notch2, which exhibit the highest structural similarity among the four mammalian Notch receptors. Possibly due to its more restricted tissue distribution, targeted deletion of murine Notch3 does not lead to embryonic lethality as is observed with targeted deletion of Notch1 and Notch2. However, genetic mutation, amplification and deregulated expression of Notch3 have been correlated with the disruption of cell differentiation in transgenic mice and to development of diseases in mice and humans. This review discusses the possible relationships between the structural differences and the nonredundant roles that Notch3 plays in the pathogenesis of the human disease cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy and in the regulation of murine T-cell differentiation and leukemogenesis
Prostaglandin E2 inhibits the interleukin-2 promoter activity through down-regulation of the oct-dependent transcription of the octamer motif.
No full textProstaglandins, mainly those of the E series (PGE), are modulators of immune responses. Indeed PGE(2) inhibits T cell activation and the transcription of the interleukin-2 (IL-2) gene, the major T cell growth factor, We observed that PGE(2) inhibits IL-2 promoter transcription activity by interfering with signals activating the (-96 to -66 bp) octamer motif. This motif binds Oct-1 and Oct-2 as well as the phorbol ester and calcium ionophore-inducible jun and fos AP-1 factors. The PGE(2)-dependent down-modulation is observed in the presence of either the endogenous transacting factor Oct-1 or the exogenously expressed Oct-2. PGE(2) does not regulate octamer function by influencing the jun and fos mRNA or Oct-1 protein levels or their DNA-binding abilities. Functional dissection of the octamer motif, through mutations of either the AP-1 or the octamer sites, revealed that the AP-1 site is dispensable for PGE(2)-dependent inhibition which instead may occur through the interference with the Oct-mediated transactivation of the octamer element, Our data suggest that the Oct-octamer interaction is a novel target of the PGE(2)-induced down-regulation of the IL-2 promoter, (C) 1996 Academic Press, Inc
Notch3 and pre-TCR interaction differentially regulate T cell development and leukemogenesis
No full textCombinatorial interaction among signaling pathways is believed to determine hemopoietic cell fate. Notch proteins are a wide-expressed family of transmembrane receptors that have been shown to influence cell fate decisions and tumorigenesis in multiple systems, including T cells. We previously generated Notch3-IC transgenic mice and demonstrated that altered Notch3 signaling impairs the developmentally regulated interplay between pre-TCR and NF-jB signalling and allows the disruption of thymocyte differentiation and the development of T cell leukaemia. Moreover, by utilizing Notch3-IC transgenic mice and Notch3-IC/pTa-/- double mutant mice, which do not develop leukemia, we demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for Notch3-induced thymocyte differentiation. We will discuss new genetic and biochemical evidence that Notch3, depending on its interaction with pre- TCR, triggers multiple NF-jB activation pathways and regulates SCL/Tal1 and Ikaros transcription factor functions, thus regulating early T cell differentiation and leukemogenesis. We also will show that cooperation between Notch3 and pTa appears to be required for correct development and function of T regulatory cells, thus suggesting its role in lineage fate decision
Deletion of NF-kappa/p50 influences the outcome of Notch3-dependent T cell leukemia
No full textThe deregulation of Notch3 signaling inside T-cell compartment of transgenic (N3-tg) mice, induces an aggressive form of T-cell acute lymphoblastic lymphoma (T-ALL), sustained by a constitutive activation of the NF-B canonical pathway, mainly represented by the p50/p65 heterodimer. To clarify the Notch/NF-B relationships in the development of T-ALL, we generated double mutant mice, deleted of the NF-B/p50 subunit in a Notch3 transgenic background (N3-tg/p50-/-). The follow-up of N3-tg/p50-/- versus N3-tg mice revealed that p50 deletion strongly inhibits the development of Notch3-dependent T-ALL. Surprisingly, double mutant succumb earlier than N3-tg mice, displaying the trait of a myeloproliferative disease, with an aberrant accumulation of Mac1+Gr1+ myeloid cells in both spleen and peripheral blood, as well as of granulocyte/monocyte progenitors in the bone marrow. Our preliminary results suggest that Notch3 overexpression in T-cell compartment is able to influence, possibly in trans, the equilibrium of the myeloid compartment and that the ablation of NF-B canonical pathway may impact on the outcomes of a T-cell specific deregulation of Notch signaling. We provide a useful experimental model to extend our understanding of Notch/NF-B interplay in hemopoietic system and to unravel novel relationships between lymphoid and myeloid differentiation
Notch3 sustains CXCR4 expression in acute T cell lymphoblastic leukemia progression
No full textIntroduction: Acute T cell lymphoblastic-leukemia (T-ALL) is the most common of childhood cancers. The majority of T-ALL cases are driven by Notch deregulated signaling, that activates different downstream pathways essential for TALL cell proliferation and leukemia-initiating cell (LIC) activity. The oncogenic function of Notch3 in T-ALL was demonstrated by a murine model of our laboratory, characterized by enforced expression of the Notch3 receptor active form (N3-IC) in immature thymocytes (N3-ICtg). Aberrant proliferation and maturation at the preT/T transition phase and constitutive activation of preTCR and NF-kB signalings were observed in N3-ICtg mice. Multiple signals from stroma sustain T cell differentiation programs in the (DN) to Double Positive (DP) thymocytes. The stromal cell derived factor SDF-1 (CXCL12) and its receptor CXCR4 promote survival of DN thymocytes and regulate the migration during the DN/DP transition. The CXCR4/SDF-1 axis has been recently suggested to play a role in the pathogenesis of T-ALL.
Material and Methods: CXCR4 and Notch3 cell-surface evalution was performed by FACS analysis with freshly isolated DP T cells obtained from thymus, blood, spleen and bone marrow of N3-ICtg and wt mice. Statistical analysis of the data was performed. Biochemical analysis of the modulatory effect of Notch3 overexpression in TALL1, a human leukemic CD3+/CD4+/CD8+ cell line, was performed by FACS, RealTime-PCR and Western Blot.
Results and Discussion: In Notch3-ICtg mice, DP-gated thymocytes display an increased level of CXCR4 expression per cell with respect to wt. Furthermore, most of the DP thymocytes highly co-express Notch3 and CXCR4. Abnormally represented DP T cells at different ages in lymphoid organs of N3-ICtg show a combined Notch3/CXCR4 expression suggesting a crosstalk of the two receptors, possibly modulating their leukemogenicity. Through inhibition of Notch signaling (GSI treatment) or by silencing Notch3 gene expression (shRNA) we could modulate CXCR4 cell-surface expression in TALL1 (CD4+/CD8+/CD3+ leukemic cell line).
Conclusion: Overall, our results are suggestive of Notch3 deregulated pathway as a molecular mechanism that may modulate DP T cells egress from thymus, in early steps of T-ALL development, by forcing CXCR4 cell-surface expression through a beta-arrestin-mediated mechanism
Identification of an estrogen-mediated deoxyribonucleic acid-binding independent transactivation pathway on the epidermal growth factor receptor gene promoter.
No full textTo investigate the estrogenic effects on the transcriptional regulation of the epidermal growth factor (EGF) receptor (EGFR) gene, we assayed its promoter ability to direct transcription of the luciferase reporter gene after transfection into HeLa cells. Our studies demonstrated a dose-dependent activation of the EGFR gene transcription by ligand-bound estrogen receptor alpha (ERalpha). This action was retained by the 36-bp core promoter fragment and did not require the receptor DNA binding domain, as demonstrated by analyzing the role of ERalpha deletion mutants on EGFR gene promoter-derived constructs. The 36-bp promoter fragment does not contain an estrogen response element but an imperfect thyroid hormone response element half-site that overlaps the Sp1 binding site. ERalpha does not bind this imperfect thyroid hormone response element half-site but is able to enhance binding of Sp1 to its site, in gel mobility shift assays, suggesting that the mechanism by which the receptor stimulated the transcription involved protein-protein interactions that replaced DNA binding. To explain this action, we propose a model in which induction of the EGFR gene expression by estrogens in HeLa cells is dependent upon the formation of a transcriptionally active ERalpha-Sp1 complex that binds to the GC-rich (Sp1) region of the minimal promoter
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