AML1/Runx1 recruits calcineurin to regulate granulocyte macrophage colony-stimulating factor by Ets1 activation.
| العنوان: | AML1/Runx1 recruits calcineurin to regulate granulocyte macrophage colony-stimulating factor by Ets1 activation. |
|---|---|
| المؤلفون: | Liu, Hebin, Holm, Magnus, Xie, Xiao-Qi, Wolf-Watz, Magnus, Grundström, Thomas |
| المصدر: | Journal of Biological Chemistry. 279(28):29398-29408 |
| مصطلحات موضوعية: | Animals, Calcineurin/genetics/*metabolism, Calcium/metabolism, Core Binding Factor Alpha 1 Subunit, Core Binding Factor Alpha 2 Subunit, Cyclosporine/pharmacology, DNA-Binding Proteins/genetics/*metabolism, Enhancer Elements (Genetics), Enzyme Inhibitors/pharmacology, Gene Expression Regulation/drug effects, Genes, Reporter, Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism, Granulocyte-Macrophage Colony-Stimulating Factor/genetics/*metabolism, Humans, Ionomycin/pharmacology, Ionophores/pharmacology, Jurkat Cells, Mice, Neoplasm Proteins/genetics/metabolism, Phosphorylation, Promoter Regions (Genetics), Protein Structure, Tertiary, Protein Subunits/genetics/*metabolism, Protein Transport/physiology, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins/genetics/*metabolism, Proto-Oncogene Proteins c-ets, Transcription Factors/genetics/*metabolism |
| الوصف: | Acute myeloid leukemia 1 (AML1), also denoted Runx1, is a transcription factor essential for hematopoiesis, and the AML1 gene is the most common target of chromosomal translocations in human leukemias. AML1 binds to sequences present in the regulatory regions of a number of hematopoiesis-specific genes, including certain cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) up-regulated after T cell receptor stimulation. Here we show that both subunits of the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin (CN), which is activated upon T cell receptor stimulation, interact directly with the N-terminal runt homology domain-containing part of AML1. The regulatory CN subunit binds AML1 with a higher affinity and in addition also interacts with the isolated runt homology domain. The related Runx2 transcription factor, which is essential for bone formation, also interacts with CN. A constitutively active derivative of CN is shown to activate synergistically the GM-CSF promoter/enhancer together with AML1 or Runx2. We also provide evidence that relief of the negative effect of the AML1 sites is important for Ca(2+) activation of the GM-CSF promoter/enhancer and that AML1 overexpression increases this Ca(2+) activation. Both subunits of CN interact with AML1 in coimmunoprecipitation analyses, and confocal microscopy analysis of cells expressing fluorescence-tagged protein derivatives shows that CN can be recruited to the nucleus by AML1 in vivo. Mutant analysis of the GM-CSF promoter shows that the Ets1 binding site of the promoter is essential for the synergy between AML1 and CN in Jurkat T cells. Analysis of the effects of inhibitors of the protein kinase glycogen synthase kinase-3beta and in vitro phosphorylation/dephosphorylation analysis of Ets1 suggest that glycogen synthase kinase-3beta-phosphorylated Ets1 is a target of AML1-recruited CN phosphatase at the GM-CSF promoter. |
| وصف الملف: | |
| الوصول الحر: | https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-16489Test http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15123671&dopt=CitationTest |
| قاعدة البيانات: | SwePub |
| تدمد: | 00219258 1083351X |
|---|---|
| DOI: | 10.1074/jbc.M403173200 |