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Alan G Rosmarin - One of the best experts on this subject based on the ideXlab platform.
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GA Binding Protein transcriptionally regulates the lamin b receptor gene insight into the progression of myelodysplasia
Blood, 2010Co-Authors: Rahul Garhwal, Zhong-fa Yang, Alan G Rosmarin, Peter GainesAbstract:Abstract 2607 Pelger-Huet anomaly (PHA) is a disorder of neutrophil nuclear lobulation, in which mature human granulocytes have a mononuclear or bilobed nucleus (so-called pince-nez cells). PHA is a congenital human disorder, but nuclear hypolobation also arises as an acquired defect in pre-leukemic myelodysplastic syndromes. Lamin B receptor (LBR) is an inner nuclear membrane Protein whose expression increases during myeloid differentiation, and loss of LBR expression causes PHA. We sought to examine the regulation of LBR in order to identify molecular mechanisms that contribute to neutrophil disorders, including myelodysplastic syndromes and acute myelogenous leukemia. Many hematopoietic-specific genes are regulated by the combinatorial activity of transcription factors, including the ETS factors, PU.1 and GABP (GA Binding Protein). GABP and PU.1 cooperate to regulate the expression of the leukocyte adhesion molecule CD18, and recently were shown to regulate the expression of the interleukin-7 receptor in developing B cells. GABP is an obliGAte heterotetramer that is composed of two structurally dissimilar Proteins, GABPα and GABPβ. Our analysis of the Lbr gene promoter identified classic “GAGGAA” ets consensus sequences located proximal and distal to the Lbr transcription start site. Lbr promoter constructs containing either the proximal ets site or both the proximal and distal ets sites were not activated by PU.1, alone, following transfection into COS cells. However, these constructs were activated by co-expression of GABPα plus GABPβ, and combined expression of GABPα/β plus PU.1 further activated these constructs up to two-fold. This suggests that GABP and PU.1 cooperatively activate the Lbr gene promoter. Electrophoretic mobility shift assays (EMSA) using radiolabeled probes that include the distal or proximal putative ets sites and nuclear extracts from HEK-293 cells transfected with expression vectors for GABPα, GABPβ and PU.1, identified multiple low mobility bands that were competed by 100 fold excess of cold competitor probe, but not by an irrelevant control probe. Inclusion of anti-GABPα antibodies in the Binding reaction disrupted mobility shifts of the probes, indicating that GABPα directly interacts with the Lbr promoter and may participate in the formation of a multimeric Protein complex that binds the promoter. Similar results were observed with nuclear extracts from EML cells, which correspond to murine hematopoietic progenitor cells that can be induced to differentiate toward promyelocytic EPRO cells and thence to mature granulocytes. We examined Protein expression of GABPα in HL-60 and EML/EPRO progenitor cells, and found that GABPα is highly expressed in uninduced progenitors but downregulated during either neutrophil or monocyte differentiation. We generated mice in which loxP recombination sites flank critical exons of GAbpa ; in the presence of Cre recombinase the loxP sites undergo rearrangement and GAbpa is deleted. We bred these animals to mice that are transgenic for estrogen receptor (ER)-regulated Cre recombinase, and created a novel EML cell line from their bone marrow. Upon activating Cre expression with 4-hydroxytamoxifen, most EML cells died within 24 hours, as compared to control cells. This result is consistent with previous studies demonstrating that GABP is required for cell cycle progression, and suggests that GABP plays a critical role in myeloid cell survival. Together, our data indicate that the GABP tetramer binds to specific sequences of the Lbr promoter, and that GABP cooperates with PU.1 to drive Lbr expression during neutrophil differentiation. Analysis of promoter constructs with mutated ets sites in our reporter assays and mobility shift assays will further our knowledge about the importance of GABP/PU.1 complexes in Lbr gene regulation. EML cells that can undergo conditional deletion of GAbpa provide a powerful tool for analysis of the regulation of myeloid genes such as Lbr , and for the molecular mechanisms that cause disorders of myeloid maturation, including myelodysplastic syndromes and acute myelogenous leukemia. Disclosures: No relevant conflicts of interest to declare.
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transcriptional regulation of the nuclear envelope lamin b receptor new roles for GA Binding Protein GAbp in neutrophil development
Blood, 2009Co-Authors: Rahul Garhwal, Alan G Rosmarin, Stephanie Halene, Peter GainesAbstract:Abstract 1464 Poster Board I-487 The essential roles that neutrophils play in innate immune responses require that these phagocytes rapidly migrate to sites of infection, adhere to and escape capillary epithelium, and then engulf and destroy invading pathogens. The capacity of neutrophils to perform these complicated functions is largely dependent on the actions of multiple hematopoietic transcription factors that coordinate the expression of critical functional genes during neutrophil development. These transcription factors include CCAAT/enhancer Binding Proteins C/EBPα and C/EBPe, the ETS family Protein PU.1, and the GA Binding Protein, GABP, which is also an ETS transcription factor that acts as an obliGAte heterotetramer comprised of GABPα and GABPβ. In addition to the activation of functional genes, neutrophil progenitors in the bone marrow undergo profound morphologic changes that include the formation of lobulated nuclei. Although it is still unclear as to the precise purpose of nuclear lobulation, we and others have demonstrated that the nuclear envelope Protein called the lamin B receptor (LBR) is essential to neutrophil nuclear lobulation and that loss of Lbr expression in mouse neutrophils leads to decreased functional responses, including a reduced respiratory burst and abnormal chemotaxis. We also have shown that Lbr gene expression is upregulated during neutrophil development, indicating that the transcriptional control of Lbr expression may play a critical role in both neutrophil morphologic maturation and function. To identify the transcriptional regulators that control Lbr activation during neutrophil development, we have isolated the promoter of the mouse Lbr gene and have assessed the roles that different regulators of neutrophil development play on Lbr activation. Previous studies demonstrated that C/EBPe directly activates the Lbr promoter, but we found that myeloid C/EBPe-/- cells exhibit normal Lbr expression. We therefore focused on identifying alternative regulators that may control Lbr gene activation. We first identified two putative ets Binding sites in the Lbr gene promoter that are located near two previously identified C/EBP Binding sites. We then focused on analyzing transcriptional activities of two ETS family members known to play roles in myeloid gene activation, PU.1 and GABP, on Lbr promoter sequences that contain these ets Binding sites. Using promoter expression constructs that contain different sized regions of the Lbr gene promoter and Cos cell transfections, we confirm that C/EBPe alone does indeed drive Lbr expression, but that either C/EBPα or PU.1 alone fails to activate the Lbr promoter. In contrast, expression of GABP, via co-expression of GABPα and GABPβ, transcriptionally activates the Lbr promoter to levels observed with C/EBPe alone. Interestingly, GABP activates a short Lbr promoter that contains only one ets Binding site but that lacks C/EBPe Binding sites, indicating that a single ets site is sufficient for GABP to drive Lbr expression in the absence of C/EBPe. Furthermore, co-expression of GABP plus PU.1 significantly increased activation of the Lbr promoter to levels above that observed for either GABP alone or C/EBPe alone. This result indicates that GABP and PU.1 synergistically activate the Lbr promoter. Ongoing analyses of mutant forms of these promoter constructs will address the importance of ets Binding sites to Lbr gene activation, and Binding assays will be used to identify in vivo interactions between GABP and/or PU.1 with the Lbr promoter. We are also generating an EML cell line that contains flox Binding sites that flank GABP gene exons, which will be used to generate myeloid progenitors that lack GABP expression. Together our studies are identifying novel mechanisms that regulate the expression of a nuclear envelope Protein that is essential for neutrophil development, and may reveal important insight into how morphologic maturation of neutrophils is closely linked to neutrophil functions. Disclosures No relevant conflicts of interest to declare.
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GA-Binding Protein and p300 are essential components of a retinoic acid-induced enhanceosome in myeloid cells.
Molecular and cellular biology, 2006Co-Authors: Karen K. Resendes, Alan G RosmarinAbstract:Expression of CD18, the β chain of the leukocyte integrins, is transcriptionally regulated by retinoic acid (RA) in myeloid cells. Full RA responsiveness of the CD18 gene requires its proximal promoter, which lacks a retinoic acid response element (RARE). Rather, RA responsiveness of the CD18 proximal promoter requires ets sites that are bound by GA-Binding Protein (GABP). The transcriptional coactivator, p300, further increases CD18 RA responsiveness. We demonstrate that GABPα, the ets DNA-Binding subunit of GABP, physically interacts with p300 in myeloid cells. This interaction involves the GABPα pointed domain (PNT) and identifies p300 as the first known interaction partner of GABPα PNT. Expression of the PNT domain, alone, disrupts the GABPα-p300 interaction and decreases the RA responsiveness of the CD18 proximal promoter. Chromatin immunoprecipitation and chromosome conformation capture demonstrate that, in the presence of RA, GABPα and p300 at the proximal promoter recruit retinoic acid receptor/retinoid X receptor from a distal RARE to form an enhanceosome. A dominant neGAtive p300 construct disrupts enhanceosome formation and reduces the RA responsiveness of CD18. Thus, Proteins on the CD18 proximal promoter recruit the distal RARE in the presence of RA. This is the first description of an RA-induced enhanceosome and demonstrates that GABP and p300 are essential components of CD18 RA responsiveness in myeloid cells.
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GA Binding Protein (GABP) Is Required for Myeloid Cell Development and Differentiation.
Blood, 2005Co-Authors: Karen Drumea, Zhong-fa Yang, Alan G RosmarinAbstract:GABPα is an ets transcription factor that regulates genes that are required for innate immunity, including CD18 (β2 leukocyte integrin), lysozyme, and neutrophil elastase. GABP consists of two distinct and unrelated Proteins that, together, form a functional transcription factor complex. GABPα binds to DNA through its ets domain and forms a multimeric complex by recruiting its partner, GABPβ, which contains the transactivation domain. GABPα is a single copy gene in both the human and murine genomes and it is the only Protein that can recruit GABPβ to DNA. We cloned GABPα from a murine genomic BAC library and prepared a targeting vector in which the GABPα ets domain is flanked by loxP recombination sites (floxed allele, designated fl). Mice that bear one intact (and one disrupted copy) of GABPα, i.e. hemizygous mice, are phenotypically normal. Intercrossing of hemizygous mice yielded no nullizygous mice, indicating that homozygous loss of GABPα causes an embryonic lethal defect. To determine the effect of GABPα deletion on myeloid cell development, we bred heterozygous and homozygous floxed mice to mice that bear the interferon-responsive Mx1-Cre transgene, which express Cre in response to injection of the synthetic polynucleotide, poly I-C. Bone marrow cells underwent efficient deletion of GABPα following poly I-C injection; in contrast, other somatic tissues did not efficiently delete the floxed allele. Bone marrow, peripheral blood, and other tissues were examined for cellular morphology and flow cytometry. We compared mice that lack GABPα in bone marrow ( i.e . fl/fl Mx1-Cre mice injected with poly I-C) to littermate controls ( i.e . fl/fl mice injected with poly I-C). Mice that lack GABPα exhibited a striking and statistically significant decrease in granulocytes and monocytes in bone marrow and peripheral blood, compared with controls; in contrast, there was an increase in erythroid cells in GABPα null bone marrow. This indicates that the loss of GABPα has lineage-specific effects on myeloid cell development. Morphologic analysis indicates that mice which lack GABPα possess more immature granulocytes compared to control mice. Thus, GABP disruption causes a striking loss of myeloid cells in the bone marrow and peripheral blood of mice in a lineage-specific manner. Furthermore, the maturation block of murine granulocytes that is caused by GABPα disruption demonstrates the crucial role of GABP in myeloid differentiation.
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GABP (GA Binding Protein) Is Required for Formation of a Retinoic Acid-Induced Myeloid Enhanceosome on the CD18 Promoter.
Blood, 2005Co-Authors: Karen K. Resendes, Alan G RosmarinAbstract:CD18, the β chain of the leukocyte integrins, mediates cell-cell and cell-matrix interactions of white blood cells and is required for normal innate immunity. Retinoic acid (RA) induces maturation of myeloid cells; mutations in retinoic acid receptors (RARs) account for acute promyelocytic leukemia. CD18 is transcriptionally regulated by RA in myeloid cells. The proximal promoter of CD18 is transcriptionally regulated by RA but, strikingly, this region is not bound or activated by retinoic acid receptors. Rather, the RA-responsiveness of the CD18 proximal promoter is dependent on ets sites that are bound by the ets transcription factor, GA-Binding Protein (GABP). The transcriptional co-activator, p300, further increases the RA-responsiveness of CD18. We show that p300 and GABPα, the ets DNA Binding subunit of GABP, physically interact in myeloid cells. This interaction uses the cysteine/histidine regions of p300, and the pointed domain (PNT) of GABPα. This demonstrates p300 as the first known interaction partner of the GABPα PNT domain. We prepared a GABPα PNT domain construct for expression in mammalian cells and showed that this PNT construct inhibited the GABPα:p300 interaction and dramatically decreased the RA-responsiveness of the CD18 proximal promoter. We used Chromatin immunoprecipitation (ChIP) to demonstrate that RA induces formation of an enhanceosome on the CD18 promoter; thus, GABPα and p300 on the CD18 proximal promoter recruit RAR/RXR bound to a distal enhancer in the presence of RA. We prepared a dominant neGAtive p300 construct and showed that its expression blocks the formation of the CD18 enhanceosome. These results demonstrate that GABP is required for formation of an enhanceosome that mediates responsiveness of CD18 to RA in myeloid cells. Dominant neGAtive forms of GABPα and p300 interfere with RA responsiveness in myeloid cells and disrupt this enhanceosome. The CD18 enhanceosome is the first known RA-induced enhanceosome and demonstrates its role in mediating retinoid responsiveness in myeloid cells.
Reinhard Kurth - One of the best experts on this subject based on the ideXlab platform.
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GA Binding Protein factors in concert with the coactivator creb Binding Protein p300 control the induction of the interleukin 16 promoter in t lymphocytes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
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GA-Binding Protein factors, in concert with the coactivator CREB Binding Protein/p300, control the induction of the interleukin 16 promoter in T lymphocytes.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
Norbert Bannert - One of the best experts on this subject based on the ideXlab platform.
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GA Binding Protein factors in concert with the coactivator creb Binding Protein p300 control the induction of the interleukin 16 promoter in t lymphocytes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
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GA-Binding Protein factors, in concert with the coactivator CREB Binding Protein/p300, control the induction of the interleukin 16 promoter in T lymphocytes.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
Michael Baier - One of the best experts on this subject based on the ideXlab platform.
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GA Binding Protein factors in concert with the coactivator creb Binding Protein p300 control the induction of the interleukin 16 promoter in t lymphocytes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
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GA-Binding Protein factors, in concert with the coactivator CREB Binding Protein/p300, control the induction of the interleukin 16 promoter in T lymphocytes.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
Andris Avots - One of the best experts on this subject based on the ideXlab platform.
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GA Binding Protein factors in concert with the coactivator creb Binding Protein p300 control the induction of the interleukin 16 promoter in t lymphocytes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
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GA-Binding Protein factors, in concert with the coactivator CREB Binding Protein/p300, control the induction of the interleukin 16 promoter in T lymphocytes.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Norbert Bannert, Michael Baier, Andris Avots, Edgar Serfling, Reinhard KurthAbstract:Interleukin 16 (IL-16) is a chemotactic cytokine that binds to the CD4 receptor and affects the activation of T cells and replication of HIV. It is expressed as a large 67-kDa precursor Protein (pro-IL-16) in lymphocytes, macrophages, and mast cells, as well as in airway epithelial cells from asthmatics after challenge with allergen. This pro-IL-16 is subsequently processed to the mature cytokine of 13 kDa. To study the expression of IL-16 at the transcriptional level, we cloned the human chromosomal IL-16 gene and analyzed its promoter. The human IL-16 gene consists of seven exons and six introns. The 5′ sequences up to nucleotide −120 of the human and murine IL-16 genes share >84% sequence homology and harbor promoter elements for constitutive and inducible transcription in T cells. Although both promoters lack any TATA box, they contain two CAAT box-like motifs and three Binding sites of GA-Binding Protein (GABP) transcription factors. Two of these motifs are part of a highly conserved and inducible dyad symmetry element shown previously to control a remote IL-2 enhancer and the CD18 promoter. In concert with the coactivator CREB Binding Protein/p300, which interacts with GABPα, the Binding of GABPα and -β to the dyad symmetry element controls the induction of IL-16 promoter in T cells. Supplementing the data on the processing of pro-IL-16, our results indicate the complexity of IL-16 expression, which is tightly controlled at the transcriptional and posttranslational levels in T lymphocytes.
