17 results on '"Soeiro I"'
Search Results
2. Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes
- Author
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White, P C, Shore, A M, Clement, M, McLaren, J, Soeiro, I, Lam, E W-F, and Brennan, P
- Published
- 2006
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3. Mesenchymal stem cells inhibit immune responses by arresting T-cell proliferation in the G1 phase of the cell cycle
- Author
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Glennie, S., Soeiro, I., Lam, E., and Dazzi, F.
- Published
- 2004
4. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells
- Author
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Essafi, A., Mattos, S.F. de, Hassen, Y.A.M., Soeiro, I., Mufti, G.J., Thomas, N.S.B., Medema, R.H., Lam, E.W.-F., Essafi, A., Mattos, S.F. de, Hassen, Y.A.M., Soeiro, I., Mufti, G.J., Thomas, N.S.B., Medema, R.H., and Lam, E.W.-F.
- Published
- 2005
5. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth
- Author
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Ramasamy, R, primary, Lam, E W-F, additional, Soeiro, I, additional, Tisato, V, additional, Bonnet, D, additional, and Dazzi, F, additional
- Published
- 2006
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6. Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes
- Author
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White, P C, primary, Shore, A M, additional, Clement, M, additional, McLaren, J, additional, Soeiro, I, additional, Lam, E W-F, additional, and Brennan, P, additional
- Published
- 2005
- Full Text
- View/download PDF
7. Mesenchymal stem cells induce division arrest anergy of activated T cells
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Glennie, S.J., primary, Soeiro, I., additional, Dyson, J., additional, Lam, E., additional, and Dazzi, F., additional
- Published
- 2005
- Full Text
- View/download PDF
8. A Pilot Study Testing the Effectiveness of a Mindfulness-Based Program for Portuguese School Children.
- Author
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Magalhães S, Nunes T, Soeiro I, Rodrigues R, Coelho A, Pinheiro M, Castro SL, Leal T, and Limpo T
- Abstract
Objectives: Research into the effectiveness of mindfulness-based programs (MBPs) in school settings has grown substantially. However, studies in the field are still scarce, present methodological limitations, and fail to examine how children's characteristics influence MBPs' effects. The twofold aim of this study was to analyze the effectiveness of an MBP on children's attention and emotional regulation, writing performance, and school grades, and to evaluate the moderating role of baseline scores, age, gender, and socioeconomic status., Methods: Fifty-seven third graders received the MBP ( n = 28) or a health-based program ( n = 29), which is the active control group, for 8 weeks. In each week, both programs were composed of two 30-min sessions delivered by psychologists and three 5-min sessions delivered by teachers. Before and after the implementation of the programs, we assessed teacher-rated children's attention and emotional regulation, performance-based attention networks (alerting, orienting, and conflict monitoring), writing performance (handwriting fluency, spelling, and text quality), and school grades in Portuguese, Mathematics, and Social Studies., Results: Compared to the control group, after the program, the mindfulness group displayed higher teacher-rated attention and emotional regulation, as well as better Portuguese, Mathematics, and Social Studies grades. Emotional regulation and alerting baseline scores as well as age were found to moderate the MBP's effects., Conclusions: These findings provide preliminary evidence on the effectiveness of a MBP on children's behavior and school grades. This means that students may benefit from the integration of mindfulness practices into the educational setting as a complement to the school curriculum., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
- Published
- 2022
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9. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle.
- Author
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Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, and Dazzi F
- Subjects
- Antigens, CD analysis, Bone Marrow Cells cytology, CD4-Positive T-Lymphocytes immunology, Cell Differentiation drug effects, Cyclin D2, Cyclins genetics, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Humans, Immunophenotyping, Interleukin-4 pharmacology, Lymphocyte Activation, Monocytes cytology, Monocytes drug effects, Monocytes immunology, Monocytes physiology, Cell Cycle physiology, Cell Differentiation physiology, Dendritic Cells cytology, Dendritic Cells physiology, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells physiology
- Abstract
Background: Mesenchymal stem cells (MSCs) play a crucial role in hematopoietic development and have been shown to exert a powerful immunosuppressive effect. In this study, we investigated the effect of bone marrow MSC on the differentiation and function of peripheral blood monocytes into dendritic cells (DCs)., Methods: Human MSCs, generated from normal bone marrow, were added to peripheral blood monocytes stimulated in vitro with granulocyte-macrophage colony stimulating factor and interleukin-4 to become DCs. Monocytes were then examined for the expression of markers characteristic of DCs and their ability to stimulate allogeneic T cells. In addition, the effect of MSCs on the cell cycle of monocyte-derived DCs and the expression of various cell cycle proteins were analyzed by cytometric analysis and Western blotting with specific antibodies., Results: MSCs blocked the differentiation of monocytes into DCs and impaired their antigen-presenting ability. This resulted from a block of monocytes from entering the G1 phase of the cell cycle with a progressive number of cells accumulating in the G0 phase. Cyclin D2 was downregulated. However, differently from what was observed in T-cells stimulated in the presence of MSCs, the expression of p27 was found decreased, suggesting the involvement of similar but not identical pathways., Conclusions: We conclude that MSCs impair monocyte differentiation and function by interfering with the cell cycle. These findings imply that MSC-induced immunosuppression might be a side product of a more general antiproliferative effect.
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- 2007
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10. p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo.
- Author
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Soeiro I, Mohamedali A, Romanska HM, Lea NC, Child ES, Glassford J, Orr SJ, Roberts C, Naresh KN, Lalani el-N, Mann DJ, Watson RJ, Thomas NS, and Lam EW
- Subjects
- Animals, B-Lymphocytes cytology, B-Lymphocytes immunology, Blood Group Antigens immunology, CD3 Complex immunology, Cell Cycle, Cells, Cultured, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase Inhibitor p27 deficiency, Leukocyte Common Antigens immunology, Mice, Mice, Knockout, Protein Binding, Retinoblastoma-Like Protein p130 deficiency, Spleen cytology, Thymus Gland cytology, Thymus Gland immunology, Up-Regulation genetics, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Hematopoietic System cytology, Retinoblastoma-Like Protein p130 metabolism
- Abstract
To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.
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- 2006
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11. Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells.
- Author
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Madureira PA, Matos P, Soeiro I, Dixon LK, Simas JP, and Lam EW
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- Animals, B-Lymphocytes cytology, B-Lymphocytes metabolism, Cell Line, Cell Proliferation, Cell Survival, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Signal Transduction, Virus Latency, Apoptosis, Cell Cycle, Proto-Oncogene Proteins c-vav metabolism, Receptors, Antigen, B-Cell metabolism, Rhadinovirus metabolism, Viral Proteins metabolism
- Abstract
The MHV-68 latent protein, M2, does not have homology to any known viral or cellular proteins, and its function is unclear. To define the role played by M2 during MHV-68 latency as well as the molecular mechanism involved, we used M2 as bait to screen a yeast two-hybrid mouse B-cell cDNA library. Vav1 was identified as an M2-interacting protein in two independent screenings. Subsequent yeast two-hybrid interaction studies showed that M2 also binds to Vav2, but not Vav3, and that three "PXXP" motifs located at the C terminus of M2 are important for this interaction. The interactions between M2 and Vav proteins were also confirmed in vivo in 293T and WEHI-231 B-cells by co-immunoprecipitation assays. Rac1/GST-PAK "pull-down" experiments and Western blot analysis using a phospho-Vav antibody demonstrated that expression of M2 in WEHI-231 cells enhances Vav activity. We further showed in WEHI-231 cells that M2 expression promotes proliferation and survival and is associated with enhanced cyclin D2 and repressed p27(Kip1), p130, and Bim expression. Taken together, these experiments suggest that M2 might have an important role in disseminating the latent virus during the establishment and maintenance of latency by modulating B-cell receptor-mediated signaling events through Vav to promote B-cell activation, proliferation, and survival.
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- 2005
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12. Phosphatidylinositol 3-kinase is required for the transcriptional activation of cyclin D2 in BCR activated primary mouse B lymphocytes.
- Author
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Glassford J, Vigorito E, Soeiro I, Madureira PA, Zoumpoulidou G, Brosens JJ, Turner M, and Lam EW
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- Androstadienes pharmacology, Animals, B-Lymphocytes enzymology, B-Lymphocytes immunology, Blotting, Western, Cell Cycle immunology, Chromones pharmacology, Class I Phosphatidylinositol 3-Kinases, Cyclin D2, Cyclins genetics, Cyclins immunology, Lymphocyte Activation immunology, Mice, Mice, Knockout, Morpholines pharmacology, Phosphatidylinositol 3-Kinases immunology, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, RNA chemistry, RNA genetics, Receptors, Antigen, B-Cell immunology, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction immunology, Transcriptional Activation, Wortmannin, B-Lymphocytes physiology, Cyclins physiology, Phosphatidylinositol 3-Kinases physiology, Receptors, Antigen, B-Cell physiology
- Abstract
Induction of cyclin D2 is essential for mediating cell cycle entry in B cells activated by BCR cross-linking. In the present study we show that, like B lymphocytes lacking cyclin D2, the p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) or other components of the B cell signalosome, p110delta-null B cells fail to induce cyclin D2 and enter early G1 but not S phase of the cell cycle. The inhibitors of PI3K activity, LY294002 and Wortmannin, also abrogate cyclin D2 induction by BCR cross-linking, confirming that the class IA PI3K is necessary for cyclin D2 induction in response to BCR stimulation. Furthermore, using both p85alpha-null and p110delta-null B cells and inhibitors of PI3K, this study demonstrates for the first time, that BCR cross-linking induces cyclin D2 mRNA expression via transcriptional activation of the cyclin D2 promoter and that this transcriptional activation of cyclin D2 requires PI3K activity. Moreover, we identify a region between nucleotides -1624 and -1303 of the cyclin D2 promoter containing elements responsive to anti-IgM, which are PI3K dependent. Further characterisation of signalling intermediates downstream of the BCR revealed a perturbation of MAPK signalling pathways in p85alpha-null and p110delta-null B cells, and our data suggests that cross-talk exists between the PI3K and JNK pathways.
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- 2005
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13. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.
- Author
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Glennie S, Soeiro I, Dyson PJ, Lam EW, and Dazzi F
- Subjects
- Animals, B-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Division immunology, Cyclin D2, Cyclins metabolism, DNA biosynthesis, Down-Regulation immunology, Flow Cytometry, G1 Phase immunology, Mesoderm cytology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Resting Phase, Cell Cycle immunology, Bone Marrow Cells cytology, CD4-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes cytology, Cell Communication immunology, Lymphocyte Activation
- Abstract
It has been shown that mesenchymal stem cells (MSCs) induce T cells to become unresponsive. We characterized the phenotype of these T cells by dissecting the effect of MSCs on T-cell activation, proliferation, and effector function. For this purpose, an in vitro murine model was used in which T-cell responses were generated against the male HY minor histocompatibility antigen. In the presence of MSCs, the expression of early activation markers CD25 and CD69 was unaffected but interferon-gamma (IFN-gamma) production was reduced. The inhibitory effect of MSCs was directed mainly at the level of cell proliferation. Analysis of the cell cycle showed that T cells, stimulated in the presence of MSCs, were arrested at the G1 phase. At the molecular level, cyclin D2 expression was profoundly inhibited, whereas p27(kip1) was up-regulated. When MSCs were removed from the cultures and restimulated with the cognate peptide, T cells produced IFN-gamma but failed to proliferate. The addition of exogenous interleukin-2 (IL-2) did not restore proliferation. MSCs did not preferentially target any T-cell subset, and the inhibition was also extended to B cells. MSC-mediated inhibition induces an unresponsive T-cell profile that is fully consistent with that observed in division arrest anergy.
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- 2005
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14. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells.
- Author
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Essafi A, Fernández de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, Medema RH, and Lam EW
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- Animals, Apoptosis Regulatory Proteins, Base Sequence, Bcl-2-Like Protein 11, Benzamides, Cell Line, Cell Line, Tumor, DNA, Forkhead Box Protein O1, Forkhead Transcription Factors, Humans, Imatinib Mesylate, Mice, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Small Interfering, Apoptosis drug effects, Carrier Proteins genetics, DNA-Binding Proteins physiology, Fusion Proteins, bcr-abl metabolism, Membrane Proteins genetics, Piperazines pharmacology, Proto-Oncogene Proteins genetics, Pyrimidines pharmacology, Transcription Factors physiology, Transcription, Genetic physiology
- Abstract
In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. Using reporter gene assays, we demonstrate that STI571 and FoxO3a activate Bim transcription through a FoxO-binding site (FHRE) located within the promoter. This was verified by DNA pull-down and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to induction of Bim expression and apoptosis. Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. Together, the results presented clearly confirm FoxO3a as a key regulator of apoptosis induced by STI571, and show that Bim is a direct transcriptional target of FoxO3a that mediates the STI571-induced apoptosis. Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis.
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- 2005
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15. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism.
- Author
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Fernández de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, Martino A, Nelson BH, Francis JM, Jones MC, Brosens JJ, Coffer PJ, and Lam EW
- Subjects
- Base Sequence, Benzamides, Binding Sites genetics, Cell Line, Cyclin D2, Cyclins metabolism, DNA, Complementary genetics, DNA-Binding Proteins genetics, Forkhead Box Protein O1, Forkhead Transcription Factors, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, Milk Proteins genetics, Nuclear Proteins metabolism, Phosphorylation, Piperazines pharmacology, Promoter Regions, Genetic, Protein Binding, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-bcl-6, Pyrimidines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering genetics, STAT5 Transcription Factor, Signal Transduction, Trans-Activators genetics, Transcription Factors genetics, Transcription, Genetic drug effects, Cyclins genetics, DNA-Binding Proteins metabolism, Fusion Proteins, bcr-abl metabolism, Milk Proteins metabolism, Trans-Activators metabolism, Transcription Factors metabolism
- Abstract
Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms whereby FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 results in down-regulation of cyclin D2 expression, activation of FoxO3a activity, and up-regulation of BCL6 expression. Using reporter gene assays, we demonstrate that STI571, FoxO3a, and BCL6 can repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. We propose that BCR-ABL inhibition leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through this STAT5/BCL6 site. This process was verified by mobility shift and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels. Furthermore, silencing of FoxO3a and BCL6 in BCR-ABL-expressing cells abolishes STI571-mediated effects on cyclin D2. This report establishes the signaling events whereby BCR-ABL signals are relayed to cyclin D2 to mediate cell cycle progression and defines a potential mechanism by which FoxO proteins regulate cyclin D2 expression.
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- 2004
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16. Cyclin D2 controls B cell progenitor numbers.
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Mohamedali A, Soeiro I, Lea NC, Glassford J, Banerji L, Mufti GJ, Lam EW, and Thomas NS
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- Animals, Antigens, CD19 metabolism, Antigens, Differentiation metabolism, B-Lymphocytes drug effects, Blotting, Western, Bone Marrow metabolism, CD5 Antigens analysis, CD5 Antigens metabolism, Cell Count, Cells, Cultured, Colony-Forming Units Assay, Cyclin D2, Cyclin D3, Cyclins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Oncogene Proteins metabolism, Phosphorylation, Proto-Oncogene Proteins c-bcr, Retinoblastoma Protein metabolism, Signal Transduction, B-Lymphocytes cytology, Cyclins physiology, Hematopoietic Stem Cells cytology, Protein-Tyrosine Kinases, Proto-Oncogene Proteins
- Abstract
Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2-/- and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2-/- mice. In addition, the colonies from cyclin D2-/- mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2-/- and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2-/- mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.
- Published
- 2003
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17. BCR targets cyclin D2 via Btk and the p85alpha subunit of PI3-K to induce cell cycle progression in primary mouse B cells.
- Author
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Glassford J, Soeiro I, Skarell SM, Banerji L, Holman M, Klaus GG, Kadowaki T, Koyasu S, and Lam EW
- Subjects
- Adaptor Proteins, Signal Transducing, Agammaglobulinaemia Tyrosine Kinase, Amides pharmacology, Animals, Antibodies, Anti-Idiotypic immunology, Apoptosis, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Calcium Signaling drug effects, Calcium Signaling physiology, Carrier Proteins physiology, Cell Cycle physiology, Chromones pharmacology, Class Ib Phosphatidylinositol 3-Kinase, Crosses, Genetic, Cyclin D2, Cyclins genetics, Enzyme Inhibitors pharmacology, Female, Imidazoles pharmacology, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes immunology, Indoles pharmacology, Ionomycin pharmacology, Isoenzymes antagonists & inhibitors, Isoenzymes deficiency, Isoenzymes genetics, Macromolecular Substances, Male, Maleimides pharmacology, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Mutant Strains, Models, Immunological, Morpholines pharmacology, Nitriles pharmacology, Phenotype, Phosphatidylinositol 3-Kinases deficiency, Phosphatidylinositol 3-Kinases genetics, Phosphoinositide-3 Kinase Inhibitors, Phospholipase C gamma, Phosphoproteins physiology, Phosphorylation, Protein Interaction Mapping, Protein Processing, Post-Translational, Protein Subunits, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases deficiency, Protein-Tyrosine Kinases genetics, Signal Transduction drug effects, Tetradecanoylphorbol Acetate pharmacology, Type C Phospholipases physiology, src-Family Kinases physiology, B-Lymphocytes pathology, Cyclins biosynthesis, Immunologic Deficiency Syndromes pathology, Isoenzymes physiology, Phosphatidylinositol 3-Kinases physiology, Protein-Tyrosine Kinases physiology, Receptors, Antigen, B-Cell physiology, Signal Transduction physiology
- Abstract
The p85alpha subunit of PI3-K and Btk are two crucial components of the B-cell receptor (BCR) signalling pathway. In the present study, we showed that primary splenic B cells from p85alpha null and xid (Btk-deficient) mice fail to induce cyclin D2 expression and enter early G1, but not S phase of the cell cycle in response to BCR engagement. Furthermore, these Btk or p85alpha null B cells displayed increased cell death compared with wild type following BCR engagement. These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCgamma (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis. Collectively, these data provide evidence for the concept that the B-cell signalosome (p85alpha, Btk, BLNK and PLCgamma) is involved in regulating cyclin D2 expression in response to BCR engagement. PKC and intracellular calcium are two major downstream effectors of the B-cell signalosome and can be activated by PMA and ionomycin, respectively. In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression. Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca(2+) entry (SK&F 96365) or PKC (Gö6850). Our present results lead us to propose a model in which the B-cell signalosome targets cyclin D2 via the Ca(2+) and PKC-dependent signalling cascades to mediate cell-cycle progression in response to BCR engagement.
- Published
- 2003
- Full Text
- View/download PDF
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