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AML1/Runx1 recruits...
AML1/Runx1 recruits calcineurin to regulate granulocyte macrophage colony-stimulating factor by Ets1 activation.
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- Liu, Hebin (författare)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Grundström
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- Holm, Magnus (författare)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Grundström
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- Xie, Xiao-Qi (författare)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Grundström
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- Wolf-Watz, Magnus (författare)
- Umeå universitet,Kemiska institutionen
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- Grundström, Thomas (författare)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Grundström
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(creator_code:org_t)
- 2004
- 2004
- Engelska.
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:28, s. 29398-29408
- Relaterad länk:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- 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
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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