NFAT4 is expressed in primary astrocytes and activated by glutamate

Jones, Elizabeth A.; Sun, Doug; Kobierski, Linda A.; Symes, Aviva J.

doi:10.1002/jnr.10584

Cited by 20 publications

(30 citation statements)

References 51 publications

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“…These events were blocked by CsA and EGTA, and overexpression of NFAT1 enhanced ionomycin-stimulated BACE1 promoter activity. NFAT1 has been found in the brain and in neuronal cells (Plyte et al, 2001), and NFAT4 is expressed and activated in astrocytes in the presence of elevated intracellular calcium (Jones et al, 2003). Interestingly, although we found both NFAT1 and NFAT4 in SH-SY5Y cells and primary cortical cultures, only NFAT1 was activated by disruption of intracecullar calcium levels.…”

Section: Discussionmentioning

confidence: 47%

“…Although NFAT was first identified in T cells, recent studies have demonstrated NFAT protein expression in other immune-related cells, as well as in many other tissues, including the spleen, thymus, lymph node, and brain (Ochi et al ., 1994;Masuda et al ., 1995;Plyte et al ., 2001;Eberl & Littman, 2003). In the brain, NFAT1 is normally detected in neuronal cells (Plyte et al ., 2001), and NFAT4 is also expressed and activated in astrocytes in the presence of elevated intracellular calcium (Jones et al ., 2003), inducing target gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling

et al. 2007

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SummaryBeta-site APP-cleaving enzyme 1 (BACE1) expression is elevated in the brains of Alzheimer's disease (AD) patients and in aged-animal models. Because both AD and aging are associated with disrupted calcium homeostasis, we investigated the role of nuclear factor of activated T cells (NFAT) -a transcription factor regulated by the calciumand calmodulin-dependent phosphatase calcineurin -in BACE1 expression. BACE1 expression was stimulated by a calcium ionophore in primary cortical cultures, and by SH-SY5Y neuroblastoma cells, which was both blocked by pretreatment with either cyclosporin A, an inhibitor of calcineurin, or ethyleneglycotetraacetic acid, a calcium chelator. Gel shift assays revealed direct binding of NFAT1 to specific DNA sequences within the BACE1 gene promoter region. Treatment with amyloid beta (Aβ β β β ), one of the major factors in AD pathogenesis, stimulated activation and nuclear translocation of NFAT1 following up-regulation of BACE1 expression. In addition, primary cortical cultures from Tg2576 mouse brains generated more Aβ β β β by ionophore stimulation, which was reversed by cyclosporin A treatment. Furthermore, NFAT1 activation was observed in Tg2576 mouse brains. These results suggest that calcium ionophore-or Aβ β β β -induced increases in intracellular calcium concentration stimulate BACE1 expression, resulting in accelerated Aβ β β β generation, and that this process is mediated through the calcineurin-NFAT1 signaling pathway. This process may play a significant role in the pathogenesis of AD and aging.

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling

et al. 2007

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“…However, both Cn (65) and NFAT4 (66) expression has been described in astrocytes. NFAT4 is activated by glutamate-mediated Ca 2ϩ increase (66), and Cn signaling mediated survival of reactive astrocytes (65). In neurons, Tat activates PI3K (67), increases levels of inositol 1,4,5-triphosphate, releases calcium from inositol 1,4,5-triphosphate-sensitive endoplasmic reticulum internal stores, and increases activity of the protein kinase C isoforms ␣, -, and (68).…”

Section: Discussionmentioning

confidence: 99%

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Blanco

Álvarez

Fresno

et al. 2008

The Journal of Immunology

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Both the HIV-1 protein Tat and cyclooxygenase-2 (COX-2) have been involved in the neuropathogenesis associated with HIV-1 infection. However, the relationship among them has not been addressed. Here, we found that extracellular Tat was able to induce COX-2 mRNA and protein expression and PGE2 synthesis in astrocytoma cell lines and primary human astrocytes. Moreover, Tat induced COX-2 promoter transcription. Deletion of NF-κB sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-κB activity, suggesting that NF-κB was not necessary to control COX-2 transcription induced by Tat. In contrast, deletion or mutation of the NFAT and/or AP-1 site abrogated COX-2 induction by Tat. Moreover, Tat induced transcription of NFAT- and AP-1-dependent reporter genes. Transfection of a dominant negative c-Jun mutant protein, TAM-67, or of a dominant negative version of NFAT, efficiently blocked the induction of COX-2 promoter by Tat, confirming the requirement of both transcription factors. Moreover, Tat induced NFAT translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NFAT and AP-1 in COX-2 induction and PGE2 synthesis by Tat was corroborated by using pharmacological inhibitors of the NFΑΤ, ERK, and JNK pathways. In summary, our results indicate that HIV-1 Tat was able to induce COX-2 and PGE2 synthesis in astrocytic cells through an NFAT/AP-1-dependent mechanism.

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“…5D). Furthermore, expression of ⌬CnA blocked the increase in the levels of NFBp65 and NFAT4 (an isoform found in astrocytes) (Jones et al, 2003) elicited by 16 h of exposure to LPS or 3 h after TNF-␣ (data not shown) in mock-transfected astrocytes (Fig. 5E) (supplemental Fig.…”

Section: Calcineurin Inhibits a Canonical Proinflammatory Pathway In mentioning

confidence: 90%

Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals

Fernández¹,

Fernández²,

Carrero³

et al. 2007

J. Neurosci.

126

147

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Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-␣ (TNF-␣) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor B (NFB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti-inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-␣ or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression.

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NFAT4 is expressed in primary astrocytes and activated by glutamate

Cited by 20 publications

References 51 publications

Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling

Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals

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