CREB function is required for normal thymic cellularity and post‐irradiation recovery

Baumann, Sven; Kyewski, Bruno; Bleckmann, Susanne C.; Greiner, Erich F.; Rudolph, Dorothea; Schmid, Wolfgang; Ramsay, Robert G.; Krammer, Peter H.; Schütz, Günther; Mantamadiotis, Theo

doi:10.1002/eji.200324826

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…This was surprising, as this is the first cell type in which we have found that the MAPK-dependent induction of these genes is independent of MSK-mediated CREB phosphorylation. Recently, a T cell-specific CREB knockout on an ATF1-null background was reported [46]. Consistent with our results, this report found no evidence in T cells for the involvement of CREB in the induction of several IE genes, including c-fos, in response to stimulation with PMA and ionomycin.…”

Section: Discussionsupporting

confidence: 88%

“…Total CREBknockout mice, which die shortly after birth, were reported to have an impaired transition from DN to DP cells and reduced TCRb expression in the embryonic thymus [50]; it is unclear whether this was due to a primary defect in the T cells or a deficiency in stromal support. However, analysis of a T cell-specific CREB/ total ATF1-knockout demonstrated that CREB is not essential for T cell development, but a reduced number of thymocytes were observed in the mice [46]. Overexpression of a CREB Ser133Ala mutation also resulted in decreased thymocyte proliferation; however, these mice exhibited additional phenotypes, such as reduced gene induction and increased apoptosis, compared to the CREB-knockout mice [28].…”

Section: Discussionmentioning

confidence: 96%

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MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

et al. 2007

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Stimulation of the T cell receptor activates the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) cascades. We demonstrate that TCR stimulation also activates the mitogen-and stress-activated kinases (MSK) downstream of ERK1/2 and p38 in both a T cell line and primary peripheral T cells. MSK1/2-knockout mice were found to have normal numbers of T cells in the thymus, and development of these cells appeared unaffected. Using naive T cells and T lymphoblasts from MSK1/2-knockout mice, it was found that MSK was the kinase responsible for phosphorylation of the transcription factor CREB in response to TCR stimulation. Phosphorylation of CREB by MSK has been linked to the transcription of nur77, nor1 and c-fos downstream of MAPK signalling in various cell types. In T cells, the TCR-dependent transcription of these genes was found to require a MAPK-dependent but MSK-independent signalling pathway. Nevertheless, the number of T cells present in the spleens of MSK1/2-knockout mice and the IL-2-induced proliferation of these cells was reduced compared to wild-type mice. This correlated to a reduction in the TCR-induced up-regulation of the IL-2 receptor CD25 and a requirement for MSK in IL-2-induced CREB phosphorylation.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

et al. 2007

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“…This finding was somewhat unexpected because a recent analysis of mice in which CREB and ATF-1 had been deleted selectively in T cells showed IL-4 expression to be preserved (31). However, a significant proportion of spleen and lymph node T cells (24 and 12%, respectively) in the knock-out mice still expressed CREB, raising the possibility that residual CREB activity was sufficient to support IL4 mRNA expression in that experimental model.…”

Section: Discussionmentioning

confidence: 47%

Functional Dissection Identifies a Conserved Noncoding Sequence-1 Core That Mediates IL13 and IL4 Transcriptional Enhancement

Strempel

Vercelli

2007

Journal of Biological Chemistry

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Conserved noncoding sequence (CNS)-1 has been shown to coordinately regulate the expression of the Th2 cytokine genes IL4, IL13, and IL5. We have used the interaction between CNS-1 and the human IL13 and IL4 promoters as a model to pursue the molecular mechanisms underlying CNS-1-dependent regulation of Th2 cytokine gene transcription. CNS-1 potently enhanced the activity of IL13 and IL4 promoter reporter vectors upon full T cell activation. Analysis of CNS-1 deletion mutants mapped enhancer activity to a short core (CNS-1-(270 -337)) that contains three closely spaced cyclic AMP-responsive elements (CRE). CRE site 2 bound CRE-binding protein (CREB) and activating transcription factor (ATF)-2 in vitro and was essential for CNS-1-dependent up-regulation of IL13 transcription. Cotransfection of an IL13 reporter construct with expression vectors for wild type or mutant CREB and ATF-2 showed that CREB, but not ATF-2, regulates CNS-1 enhancer activity. Notably, chromatin immunoprecipitation analysis showed T cell activation recruits CREB and the coactivator CREB-binding protein (CBP)/p300 to the endogenous CNS-1. Moreover, CBP/ p300 activity was essential for CNS-1-mediated enhancement of IL13 transcription. Collectively, these data define the region within CNS-1 responsible for enhancement of IL13 and IL4 transcription and suggest CREB/CBP-dependent mechanisms play an important role in facilitating Th2 cytokine gene expression in response to T cell receptor signaling. Dysregulated expression of the cytokines IL2 -4, IL-13, and IL-5 in CD4 T cells of the Th2 lineage plays a pivotal role in the pathogenesis of allergic inflammation. The IL4, IL13, and IL5 genes, closely arrayed within 150 kb of human chromosome 5q31 and the syntenic region of mouse chromosome 11, typically demonstrate coordinated expression (1, 2), a feature critical for the emergence of a bona fide allergic phenotype in experimental and clinical models. However, the molecular mechanisms underlying the concerted expression of Th2 cytokines remained elusive despite intense investigation.A breakthrough came as a result of comparative genomics analyses to identify noncoding regions highly conserved (Ն70% identity) between humans and evolutionarily distant mammalian species (3). These elements, abundant in the human genome, display characteristics indicative of regulatory function. In particular, they tend to demonstrate higher selective constraint than genomic regions that encode translated or noncoding RNAs (4, 5) and contain short, alternating stretches of sequence with high or low divergence, a pattern typical of protein-binding sites (5).The search for highly conserved noncoding sequences in ϳ1 Mb of human chromosome 5q31 identified several elements (3). The largest of these, conserved noncoding sequence (CNS)-1, mapped within the IL4/IL13 intergenic region of the Th2 cytokine locus. Deletion of CNS-1, either from a transgene or the native murine locus, led to a marked decrease in the expression of all three cytokine genes (3, 6), establishing CNS-1 ...

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“…After searching in the PubMed, we came to know the key roles of each protein and its possible relationship with immunity or dendritic cells. We classified the proteins into 7 categories, including cell division, cell signaling or communications, cell structure or motility, cell or organism defense, gene or protein expression, metabolism, and unclassified [26][27][28][29][30][31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

“…To avoid the decrease in PCR volume and keep the same amount of PCR volume in each Eppendorf tube, mineral oil was added. For semi-quantitative PCR, 4 different cycles were amplified for the 4 tubes (18,23,28,33) to compare the PCR yield. The forward primer of G3PDH is CTC CCA CTC TTC CAC CTT CGA TGC, and the reverse primer is CCT CTC TTG CTC AGT GTC CTT GCT (Supporting data, Table S1).…”

Section: Rt-pcr and Semi-quantitative Rt-pcrmentioning

confidence: 99%

The genetic profiling of preferentially expressed genes in murine splenic CD8α+ dendritic cells

Bai

et al. 2011

Immunol Res

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In the murine splenocytes, CD8α+ dendritic cells (abbreviated as 8+DC) and CD8α- dendritic cells (abbreviated as 8-DC) are identified with some vague features for each of them. 8+DCs but not 8-DCs cross-prime cytotoxic T cells in vivo. We aim to distinguish the two subtypes of DC based on gene expression profiling. Suppressive subtractive hybridization was undertaken to get differentially expressed genes from such subtracted cDNA library specific to 8+DC. A total of 114 sequences from the subtracted cDNA library specific to 8+DC library were analyzed. Most of them are known proteins, but some of them were novel, either totally novel genes or homologs to known genes, but with novel exon. About 55 probably novel exons were discovered, and 11 exons had longer length than those in gene bank. The clones 12, 44, 79, and 110 have no match with known sequences in gene bank. Then, semi-quantitative PCR was done to compare the expression of the enriched sequences between 8+DC and 8-DC. About 14 genes are differentially expressed in 8+DC. Therefore, SSH is an effective method to clone differentially expressed genes for 8+DC compared to 8-DC.

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CREB function is required for normal thymic cellularity and post‐irradiation recovery

Cited by 19 publications

References 46 publications

MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

Functional Dissection Identifies a Conserved Noncoding Sequence-1 Core That Mediates IL13 and IL4 Transcriptional Enhancement

The genetic profiling of preferentially expressed genes in murine splenic CD8α+ dendritic cells

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