Microarray Experiments for mice lacking or with the Stat5a and 5b genes in blood cells that were treated w/o CMP
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: WeiPing Chen
PROVIDER: E-GEOD-14698 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:GM-CSF controls the development of granulocytes but little is known about the contribution of the downstream mediating transcription factor STAT5A/B. To elucidate this pathway, we generated mice lacking the Stat5a and 5b genes in blood cells. Peripheral neutrophils were decreased and administration of 5-FU and GM-CSF failed to induce granulopoiesis in Stat5a/b-mutant mice. GMPs were isolated and cultured with GM-CSF. Both the number and size of STAT5A/B-null colonies were reduced and GM-CSF-induced survival of mature STAT5A/B-null neutrophils was impaired. Time-lapse cinematography and single cell tracking of GMPs revealed that STAT5A/B-null cells were characterized by a longer generation time and an increased cell death. Gene expression profiling experiments suggested that STAT5A/B directs GM-CSF signaling through the regulation of cell survival genes. Experiment Overall Design: Mice lacking or with the Stat5a and 5b genes in blood cells, which were treated w/o GMP
2009-10-10 | E-GEOD-14672 | biostudies-arrayexpress
Project description:GM-CSF controls the development of granulocytes but little is known about the contribution of the downstream mediating transcription factor STAT5A/B. To elucidate this pathway, we generated mice lacking the Stat5a and 5b genes in blood cells. Peripheral neutrophils were decreased and administration of 5-FU and GM-CSF failed to induce granulopoiesis in Stat5a/b-mutant mice. CMPs were isolated and cultured with GM-CSF.
2010-02-02 | GSE14698 | GEO
Project description:GM-CSF controls the development of granulocytes but little is known about the contribution of the downstream mediating transcription factor STAT5A/B. To elucidate this pathway, we generated mice lacking the Stat5a and 5b genes in blood cells. Peripheral neutrophils were decreased and administration of 5-FU and GM-CSF failed to induce granulopoiesis in Stat5a/b-mutant mice. GMPs were isolated and cultured with GM-CSF. Both the number and size of STAT5A/B-null colonies were reduced and GM-CSF-induced survival of mature STAT5A/B-null neutrophils was impaired. Time-lapse cinematography and single cell tracking of GMPs revealed that STAT5A/B-null cells were characterized by a longer generation time and an increased cell death. Gene expression profiling experiments suggested that STAT5A/B directs GM-CSF signaling through the regulation of cell survival genes.
2009-09-30 | GSE14672 | GEO
Project description:Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and primarily enters erythroid cells via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b-/- mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice transplanted with Stat5a/b-/- fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of erythroid progenitor iron uptake via its control of Tfr1 transcription. Experiment Overall Design: Isolated Ter119-positive fetal liver cells from three to five E14.5 embryos of the same genotype were combined, and total RNA was extracted using TRIzol reagent (Life Technologies) with two additional ethanol precipitations. RNA quality was verified using an Agilent Bioanalyzer (Agilent Technologies). Microarray analyses were performed using Affymetrix Mouse Genome 430 2.0 array GeneChips (Affymetrix). Up- and down-regulated genes were selected based on P values of <0.05 and fold changes of >1.5 or -1.5 as assessed by ANOVA using Partek Pro software (Partek). To determine specific pathways, gene pathway analysis was obtained using the statistically significant gene list (P<0.05) represented on the chip.
2008-10-21 | E-GEOD-11777 | biostudies-arrayexpress
Project description:Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B that mediate cytokine signaling. To reveal the underlying causes for this developmental block we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and their ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally-controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Taken together, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells.
2009-10-21 | GSE17723 | GEO
Project description:Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B that mediate cytokine signaling. To reveal the underlying causes for this developmental block we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and their ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally-controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Taken together, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells. The mammary tissues from two mice of each genotype were collected 6 days (sample 9 and 11 were WT)
2009-10-21 | E-GEOD-17723 | biostudies-arrayexpress
Project description:Signal Transducers and Activators of Transcription (STAT) 5A/B regulate cytokine-inducible genes upon binding to GAS motifs. It is not known what percentage of genes with GAS motifs bind to and are regulated by STAT5. Moreover, it is not clear whether genome-wide STAT5 binding is modulated by its concentration. To clarify these issues we established genome-wide STAT5 binding upon growth hormone (GH) stimulation of wild type mouse embryonic fibroblasts (MEFs) and MEFs overexpressing STAT5A more than 20-fold. Upon GH stimulation 23,827 and 111,939 STAT5A binding sites were detected in wild type and STAT5A overexpressing MEFs, respectively. 13,278 and 71,561 peaks contained at least one GAS motif. 1,586 and 8,613 binding sites were located within 2.5 kbp of promoter sequences, respectively. Stringent filtering revealed 78 genes in which the promoter/upstream region (-10kbp to +0.5kbp) was recognized by STAT5 both in wt and STAT5 overexpressing MEFs and 347 genes that bound STAT5 only in overexpressing cells. Genome-wide expression analyses identified that the majority of STAT5-bound genes was not under GH control. Up to 40% of STAT5-bound genes were not expressed. For the first time we demonstrate the magnitude of opportunistic genomic STAT5 binding that does not translate into transcriptional activation of neighboring genes. Genome-wide mapping of STAT5 binding in MEF cells (WT, KO; Stat5-/- and overexpression; STAT5A-Stat5-/-) upon growth hormone induction
2012-01-12 | E-GEOD-34986 | biostudies-arrayexpress
Project description:GM-CSF paradoxically possesses ability to differentiate both classically activated macrophages (MØs) with dominant proinflammatory function (M1-like MØs) and alternative activated MØs with strong immunosuppressive function (M2-like MØs). The intrinsic regulatory mechanism responsible for functional polarization of MØs under GM-CSF signalling remains elusive. Here we revealed that cytokine-inducible SH2-containing protein (CIS), induced by GM-CSF, is a key determinant in controlling MØ polarization. Compared to WT MØs, Cish-/- MØs gained characteristics of alternative activated MØs (M2 MØs), showing high expression of prototypic M2 markers Arginase 1, Tgm2 and YM-1; strong suppression of T cell proliferation; and low production of IL-12 and other proinflammatory cytokines¬¬. Differing from canonical IL-4/STAT6/IRF4 signaling axis of M2 induction, development of M2 MØ characteristics in Cish-/- MØs was associated with intensified STAT5 activation and consequent IRF8 downregulation. Attenuation of GM-CSF signalling via JAK inhibition and IRF8 rescue corrected certain functional defects in Cish-/- MØs. As CIS inhibition in NK and T cells promotes anti-tumour immunity, we showed that CIS deficiency enhanced the development of intra-tumoural M2 MØs and reduced CTL induction within tumour microenvironment with elevated GM-CSF. Overall, we conclude that CIS acts as an intrinsic rheostat to control intense GM-CSF signalling in order to maintain proinflammatory functions of MØs. Targeting CIS as a checkpoint in cancer immunotherapy should consider its role in regulating myeloid cell function.
2023-01-21 | PXD018390 | Pride
Project description:Inhibition of STAT5 was recently reported to reduce mouse atherosclerosis. However, the regulatory role of STAT5 isoforms STAT5A and STAT5B in human disease and more specifically in macrophages remains unknown. Here, we demonstrate reciprocal expression regulation of STAT5A and B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted NF-kB pathway, phagocytosis, cholesterol metabolism, and apoptosis terms. These changes at transcriptional level could be confirmed at functional level, with significant increases in apoptosis and phagocytosis and decreases in lipid uptake and IL-6, IL8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 inhibitor significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques. In summary, we identify STAT5A as important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target for human atherosclerotic plaque inflammation.
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Project description:GM-CSF-mediated granulopoiesis is regulated by the transcription factor STAT5A/B
| PRJNA112369 | ENA