Calcium Regulation of GM-CSF by Calmodulin-Dependent Kinase II Phosphorylation of Ets1

Liu, Hebin; Grundström, Thomas

doi:10.1091/mbc.e02-03-0149

Cited by 43 publications

(44 citation statements)

References 47 publications

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“…Since p42Ets-1 is not sensitive to this regulation, it is expected that the Ca 2 þ -regulated expression of Ets-1 target genes will switch between p51Ets-1 and p42Ets-1 depending on the Ca 2 þ status in the cell. This is most probably what happens in the regulation of the GM-CSF promoter/enhancer, which was recently shown to be directly dependent on the phosphorylation state of serine residues located in the exon VII-coded region of Ets-1 (Liu and Grundstrom, 2002) and the tumor necrosis factor-related light gene, which is also Ca 2 þ -sensitive and contains identified Ets-1-binding sites (Castellano et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

et al. 2003

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We have identified the mouse exon VII splice variant of the Ets-1 transcription factor. The variant is expressed in all cell lines which express ets-1, at lower levels, it is also expressed in the mouse embryo in vivo. The corresponding protein, p42Ets-1, is a transcription factor as it is able to bind to specific DNA sequences and to transactivate a bona fide ETS reporter vector. A comparison of optimal DNA-binding sites shows that p42Ets-1 binds to more various DNA sequences than p51Ets-1; p42Ets-1 recognizes the same optimal consensus sequence as p51Ets-1, but also many variations of it, mainly at base À1, which is located just prior to the GGAA/T core sequence. The binding differences were quantified by surface plasmon resonance analyses and the protein region responsible for the differences in DNA sequence recognition located in the Val 280 -Glu 302 fragment, which is encoded by exon VII. The specific DNA-binding properties of each isoform translates into clear differences in activity, p42Ets-1 transactivates the natural VE-cadherin gene promoter through both ETS-binding site (EBS)2 and EBS4 whereas p51Ets-1 is mainly active on EBS4. Altogether, our data suggest that p42Ets-1 acts as a distinct transcription factor from p51Ets-1. Oncogene (2003) 22, 9156-9164.

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Section: Discussionmentioning

confidence: 96%

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

et al. 2003

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“…Ca 2ϩ signaling has previously been reported to regulate positively transcription from the GM-CSF promoter/enhancer through CN activation of the transcription factors NF-AT, NF-B, and AP-1 (24,25) and negatively through Ca 2ϩ /calmodulindependent kinase II phosphorylation of serines in the autoinhibitory domain for DNA binding of Ets1 (28). In the present study, we have shown that Ca 2ϩ signaling can regulate GM-CSF transcription also through dephosphorylation that activates Ets1 by AML1/Runx protein-recruited CN.…”

Section: Discussionmentioning

confidence: 99%

“…The luciferase reporter plasmid containing a 716-bp segment of the enhancer and a 0.6-kb segment of the promoter of the human GM-CSF gene has been described previously (28). The AML1 site mutations from 5Ј-TTTGTGGTCA-3Ј to 5Ј-TTTGTAATCA-3Ј at nucleotides Ϫ59 to Ϫ50 in the promoter and from 5Ј-ATCGTGGTCC-3Ј to 5Ј-ATCGTAATCC-3Ј at nucleotides 285-294 in the enhancer were created by PCR with the PfuTurbo® polymerase.…”

Section: Methodsmentioning

confidence: 99%

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AML1/Runx1 Recruits Calcineurin to Regulate Granulocyte Macrophage Colony-stimulating Factor by Ets1 Activation

Liu

Holm

Xie

et al. 2004

Journal of Biological Chemistry

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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-3␤ and in vitro phosphorylation/dephosphorylation analysis of Ets1 suggest that glycogen synthase kinase-3␤-phosphorylated Ets1 is a target of AML1-recruited CN phosphatase at the GM-CSF promoter.

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“…Phosphorylation of 4S stabilizes the inhibitory modules, thereby reducing the DNA binding affinity, a process called auto-inhibition [6,7]. Converting 4S to alanines increases the binding of Ets-1 to GM-CSF promoter in a B cell tumor line [8]. Auto-inhibition is also alleviated by binding partners, such as Runx1 [9].…”

Section: Introductionmentioning

confidence: 99%

Role of Ets‐1 phosphorylation in the effector function of Th cells

et al. 2008

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The transcription factor Ets-1 critically regulates differentiation and function of T helper (Th) cells. In vitro studies have demonstrated that DNA binding and transcriptional activity of Ets-1 are regulated by phosphorylation. Depending on the site of phosphorylation, Ets-1 function can either be increased or inhibited. In addition, a splice variant lacking several inhibitory phosphorylation sites has been identified, raising the possibility that this splice variant may function differently from the full-length Ets-1. However, it is unclear how the activating and inhibitory phosphorylation events of Ets-1 are coordinated during Th cell activation. Furthermore, the biological consequences of Ets-1 phosphorylation and alternative splicing in regulating the function of Th cells are unknown. We report here that both activating and inhibitory phosphorylation events of Ets-1 occur simultaneously and independently of each other during Th cell activation. We further demonstrate that the effect of Ets-1 phosphorylation is very modest and that full-length Ets-1 and its splice variant are functionally interchangeable in the regulation of cytokine production in Th cells.

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Calcium Regulation of GM-CSF by Calmodulin-Dependent Kinase II Phosphorylation of Ets1

Cited by 43 publications

References 47 publications

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

AML1/Runx1 Recruits Calcineurin to Regulate Granulocyte Macrophage Colony-stimulating Factor by Ets1 Activation

Role of Ets‐1 phosphorylation in the effector function of Th cells

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