The Experts below are selected from a list of 50016 Experts worldwide ranked by ideXlab platform
Inês Soeiro - One of the best experts on this subject based on the ideXlab platform.
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regulation of Cyclin D2 and the Cyclin D2 promoter by protein kinase a and creb in lymphocytes
Oncogene, 2006Co-Authors: Paul Charles White, Inês Soeiro, Eric Lam, Angharad M Shore, Mathew Clement, James E Mclaren, Paul BrennanAbstract:Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this Cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced Cyclin D2 promoter activity 5–10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein–Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of Cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the Cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.
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Phosphatidylinositol 3-kinase is required for the transcriptional activation of Cyclin D2 in BCR activated primary mouse B lymphocytes.
European journal of immunology, 2005Co-Authors: Janet Glassford, Inês Soeiro, Elena Vigorito, Patricia A. Madureira, Georgia Zoumpoulidou, Jan J. Brosens, Martin R. Turner, Eric LamAbstract: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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foxo3a and bcr abl regulate Cyclin D2 transcription through a stat5 bcl6 dependent mechanism
Molecular and Cellular Biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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FoxO3a and BCR-ABL Regulate Cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism
Molecular and cellular biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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Cyclin D2 controls B cell progenitor numbers
Journal of leukocyte biology, 2003Co-Authors: Azim M Mohamedali, Inês Soeiro, Nicholas Lea, Janet Glassford, Lolita Banerji, Ghulam J. Mufti, Eric Lam, Shaun ThomasAbstract: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 num- bers of Sca1B220 B cell progenitors but nor- mal levels of Sca1 progenitor cells of other lin- eages. 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 (CD19 lo ) than those from Cyclin D2 / mice (CD19 Hi ). 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 coimmuno- precipitates 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, S 807/811 . We conclude that Cyclin D2 is rate- limiting for the production of B lymphoid progen- itor cells whose proliferation does not depend on BCR signaling. J. Leukoc. Biol. 74: 1139-1143; 2003.
O Miura - One of the best experts on this subject based on the ideXlab platform.
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Glycogen synthase kinase-3β and p38 phosphorylate Cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells
Oncogene, 2007Co-Authors: A Kida, K Kakihana, S Kotani, T Kurosu, O MiuraAbstract:Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating Cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes Cyclin D2 by inhibition of glycogen synthase kinase-3 β (GSK3 β ) through Janus kinase2-dependent activation of phosphatidylinositol 3′-kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of Cyclin D2, which was mediated by activation of p38. GSK3 β and p38 was demonstrated to phosphorylate Cyclin D2 on Thr280 in vitro , while a Cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of Cyclin D2 in primary leukemic or myeloma cells. These results indicate that Cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3 β or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.
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glycogen synthase kinase 3β and p38 phosphorylate Cyclin D2 on thr280 to trigger its ubiquitin proteasome dependent degradation in hematopoietic cells
Oncogene, 2007Co-Authors: A Kida, K Kakihana, S Kotani, T Kurosu, O MiuraAbstract:Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating Cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes Cyclin D2 by inhibition of glycogen synthase kinase-3β (GSK3β) through Janus kinase2-dependent activation of phosphatidylinositol 3′-kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of Cyclin D2, which was mediated by activation of p38. GSK3β and p38 was demonstrated to phosphorylate Cyclin D2 on Thr280 in vitro, while a Cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of Cyclin D2 in primary leukemic or myeloma cells. These results indicate that Cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3β or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.
Marius C Jones - One of the best experts on this subject based on the ideXlab platform.
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foxo3a and bcr abl regulate Cyclin D2 transcription through a stat5 bcl6 dependent mechanism
Molecular and Cellular Biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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FoxO3a and BCR-ABL Regulate Cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism
Molecular and cellular biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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.
Brad H Nelson - One of the best experts on this subject based on the ideXlab platform.
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foxo3a and bcr abl regulate Cyclin D2 transcription through a stat5 bcl6 dependent mechanism
Molecular and Cellular Biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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FoxO3a and BCR-ABL Regulate Cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism
Molecular and cellular biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of Cyclin D2 by the interleukin-2 receptor.
The Journal of biological chemistry, 2003Co-Authors: James J. Moon, Anthony Martino, Eric D. Rubio, Anton Krumm, Brad H NelsonAbstract:Abstract The interleukin-2 (IL-2) receptor promotes T cell proliferation in part by inducing the expression of D-type Cyclins, which enable cells to progress from the G1 to S phase of the cell cycle. We previously showed that the IL-2 receptor induces expression of Cyclin D2 by activating the transcription factor Stat5, which binds directly and immediately to a site upstream of the Cyclin D2 promoter. We show here that subsequent transcription of the Cyclin D2 gene occurs by a delayed, cycloheximide-sensitive mechanism, which implies the involvement of additional regulatory mechanisms. The transcription factor c-Myc is induced by Stat5 and is reported to bind to two E box motifs in the Cyclin D2 promoter. However, in IL-2-stimulated T cells, c-Myc does not appear to be involved in Cyclin D2 induction, since we found that these two E boxes are preferentially bound by USF-1 and USF-2 and, moreover, are dispensable for Cyclin D2 promoter activity. Instead, we found that Stat5 activates the phosphatidylinositol 3-kinase (PI3 kinase) pathway by a delayed, cycloheximide-sensitive mechanism and that PI3 kinase activity is essential for the induction of Cyclin D2 by Stat5. Chromatin immunoprecipitation experiments revealed that PI3 kinase is required for the optimal binding of RNA polymerase II to the promoters of Cyclin D2 as well as other genes. Our results reveal a novel link between PI3 kinase and RNA polymerase II promoter binding activity and demonstrate discrete, coordinated roles for the PI3 kinase and Stat5 pathways in Cyclin D2 transcription.
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Stat5 and Sp1 Regulate Transcription of the Cyclin D2 Gene in Response to IL-2
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Anthony Martino, James J. Moon, James H. Holmes, James D. Lord, Brad H NelsonAbstract:The IL-2R promotes rapid expansion of activated T cells through signals mediated by the adaptor protein Shc and the transcription factor Stat5. The mechanisms that engage the cell cycle are not well defined. We report on the transcriptional regulation of the cell cycle gene Cyclin D2 by the IL-2R. IL-2-responsive induction of a luciferase reporter gene containing 1624 bp of the Cyclin D2 promoter/enhancer was studied in the murine CD8+ T cell line CTLL2. Reporter gene deletional analysis and EMSAs indicate an IL-2-regulated enhancer element flanks nucleotide −1204 and binds a complex of at least three proteins. The enhancer element is bound constitutively by Sp1 and an unknown factor(s) and inducibly by Stat5 in response to IL-2. The Stat5 binding site was essential for IL-2-mediated reporter gene activity, and maximum induction required the adjacent Sp1 binding site. Receptor mutagenesis studies in the pro-B cell line BA/FG (a derivative of the BA/F3 cell line) demonstrated a correlation between Stat5 activity and Cyclin D2 mRNA levels when the Stat5 signal was isolated, disrupted, and then rescued. Further, a dominant-negative form of Stat5 lacking the trans-activation domain inhibited induction of Cyclin D2 mRNA. We propose that the IL-2R regulates the Cyclin D2 gene in part through formation of an enhancer complex containing Stat5 and Sp1.
Anthony Martino - One of the best experts on this subject based on the ideXlab platform.
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foxo3a and bcr abl regulate Cyclin D2 transcription through a stat5 bcl6 dependent mechanism
Molecular and Cellular Biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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FoxO3a and BCR-ABL Regulate Cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism
Molecular and cellular biology, 2004Co-Authors: Silvia Fernandez De Mattos, Inês Soeiro, Abdelkader Essafi, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C JonesAbstract: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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A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of Cyclin D2 by the interleukin-2 receptor.
The Journal of biological chemistry, 2003Co-Authors: James J. Moon, Anthony Martino, Eric D. Rubio, Anton Krumm, Brad H NelsonAbstract:Abstract The interleukin-2 (IL-2) receptor promotes T cell proliferation in part by inducing the expression of D-type Cyclins, which enable cells to progress from the G1 to S phase of the cell cycle. We previously showed that the IL-2 receptor induces expression of Cyclin D2 by activating the transcription factor Stat5, which binds directly and immediately to a site upstream of the Cyclin D2 promoter. We show here that subsequent transcription of the Cyclin D2 gene occurs by a delayed, cycloheximide-sensitive mechanism, which implies the involvement of additional regulatory mechanisms. The transcription factor c-Myc is induced by Stat5 and is reported to bind to two E box motifs in the Cyclin D2 promoter. However, in IL-2-stimulated T cells, c-Myc does not appear to be involved in Cyclin D2 induction, since we found that these two E boxes are preferentially bound by USF-1 and USF-2 and, moreover, are dispensable for Cyclin D2 promoter activity. Instead, we found that Stat5 activates the phosphatidylinositol 3-kinase (PI3 kinase) pathway by a delayed, cycloheximide-sensitive mechanism and that PI3 kinase activity is essential for the induction of Cyclin D2 by Stat5. Chromatin immunoprecipitation experiments revealed that PI3 kinase is required for the optimal binding of RNA polymerase II to the promoters of Cyclin D2 as well as other genes. Our results reveal a novel link between PI3 kinase and RNA polymerase II promoter binding activity and demonstrate discrete, coordinated roles for the PI3 kinase and Stat5 pathways in Cyclin D2 transcription.
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Stat5 and Sp1 Regulate Transcription of the Cyclin D2 Gene in Response to IL-2
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Anthony Martino, James J. Moon, James H. Holmes, James D. Lord, Brad H NelsonAbstract:The IL-2R promotes rapid expansion of activated T cells through signals mediated by the adaptor protein Shc and the transcription factor Stat5. The mechanisms that engage the cell cycle are not well defined. We report on the transcriptional regulation of the cell cycle gene Cyclin D2 by the IL-2R. IL-2-responsive induction of a luciferase reporter gene containing 1624 bp of the Cyclin D2 promoter/enhancer was studied in the murine CD8+ T cell line CTLL2. Reporter gene deletional analysis and EMSAs indicate an IL-2-regulated enhancer element flanks nucleotide −1204 and binds a complex of at least three proteins. The enhancer element is bound constitutively by Sp1 and an unknown factor(s) and inducibly by Stat5 in response to IL-2. The Stat5 binding site was essential for IL-2-mediated reporter gene activity, and maximum induction required the adjacent Sp1 binding site. Receptor mutagenesis studies in the pro-B cell line BA/FG (a derivative of the BA/F3 cell line) demonstrated a correlation between Stat5 activity and Cyclin D2 mRNA levels when the Stat5 signal was isolated, disrupted, and then rescued. Further, a dominant-negative form of Stat5 lacking the trans-activation domain inhibited induction of Cyclin D2 mRNA. We propose that the IL-2R regulates the Cyclin D2 gene in part through formation of an enhancer complex containing Stat5 and Sp1.
