Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3

Ohteki, Toshiaki; Parsons, Michael; Zakarian, Arsen; Jones, Russell G.; Nguyen, Linh T.; Woodgett, James R.; Ohashi, Pamela S.

doi:10.1084/jem.192.1.99

Cited by 150 publications

(148 citation statements)

References 33 publications

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“…The identification of GSK-3 as a key kinase in this regulation is in line with previous reports that GSK-3 is a key kinase counteracting CN in T lymphocyte activation through NF-AT (45,49). Furthermore, GSK-3 has been shown to be a negative regulator of lymphocyte activation (61), and costimulation of T cells by CD28 or by endothelial cells has been shown to activate NF-AT through inactivation of GSK-3␤ (62,63).…”

Section: Discussionsupporting

confidence: 69%

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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Section: Discussionsupporting

confidence: 69%

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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“…11,12 Lithium also stimulates T cells 13 and enhances survival of neural stem cells. 14 Thus, lithium has many effects that are potentially neuroregenerative for spinal cord injury.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial

Yang

et al. 2011

Spinal Cord

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Study design: Lithium has attracted much attention as a neuroregenerative agent for spinal cord injury in animal models. We hypothesized that the lithium can be beneficial to patients with spinal cord injury. The safety and pharmacokinetics of lithium has been studied in our earlier phase I clinical trial, indicating its safety. This is a phase II clinical trial to evaluate its efficacy on chronic spinal cord injury patients. Objectives: The aim of this study was to investigate the efficacy of lithium on chronic spinal cord injury patients. Setting: A major spinal cord injury rehabilitation center in Beijing, China. Methods: Randomized, double-blind, placebo-controlled 6-week parallel treatment arms with lithium carbonate and with placebo. A total of 40 chronic spinal cord injury subjects were recruited. Oral lithium carbonate was titrated or placebo was simulated to maintain the serum lithium level of 0.6-1.2 mmol l À1 for 6 weeks, followed by a 6-month follow-up. The functional outcomes and the neurological classifications, as well as the safety parameters, adverse events and pharmacokinetic data were carefully collected and monitored. Results: No significant changes in the functional outcomes and the neurological classifications were found. The only significant differences were in the pain assessments using visual analog scale comparing the lithium and the placebo group. No severe adverse event was documented in the study. Conclusion: The lithium treatment did not change the neurological outcomes of patients with chronic spinal cord injury. It is worth to investigate whether lithium is effective in the treatment of neuropathic pain in chronic spinal cord injury. Sponsorship: China Spinal Cord Injury Network Company Limited.

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“…Briefly, neuroblastoma cells were first treated differently, and then proteins were extracted, and GSK-3h was immunoprecipitated. Kinase activity of immunoprecipitated GSK-3h was assayed using phosphoglycogen synthase peptide-2 as substrate or glycogen synthase peptide2{Ala 21 } as a negative control peptide. The values of treated groups were normalized by the value of control group.…”

Section: Dna Vector Constructionsmentioning

confidence: 99%

Inactivation of glycogen synthase kinase-3β contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells

Tan

Thiele

2007

Molecular Cancer Therapeutics

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Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brainderived neurotrophic factor (BDNF) and its receptor TrkB are associated with poor prognosis. Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. To study targets of PI3K/ Akt that mediate protection from chemotherapy, we focused on glycogen synthase kinase-3B (GSK-3B), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3B in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3B, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3B, LiCl, GSK-3B inhibitor VII, kenpaullone, or a GSK-3B -targeted small interfering RNA (siRNA) resulted in a 15% to 40% increase in neuroblastoma cell survival after cytotoxic treatment. Transfection of neuroblastoma cells with a constitutively active GSK-3B S9A9 caused a 10% to 15% decrease in cell survival. Using realtime, dynamic measurements of cell survival, we found that 6 to 8 h after etoposide treatment was the period during which critical events regulating the induction of cell death or BDNF/TrkB-induced protection occurred. During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3B in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3B contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy. [Mol Cancer Ther 2007;6(12):3113 -21]

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Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3

Cited by 150 publications

References 33 publications

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

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

Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial

Inactivation of glycogen synthase kinase-3β contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells

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