Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

Morancho, Beatriz; Minguillón, Jordi; Molkentin, Jeffery D.; López-Rodrı́guez, Cristina; Aramburu, J.

doi:10.1186/1471-2199-9-13

Cited by 36 publications

(78 citation statements)

References 47 publications

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“…ERK2 siRNA reduces high NaCl-dependent NFAT5 transcriptional activity in nucleus pulposus [62] and in HEK293 cells [29] . It is reasonably concluded that ERK1/2, or at least ERK2, contributes to tonicity-dependent activation of NFAT5 [30] , although it is not clear why PD98059 fails to inhibit NFAT5 transcriptional activity in the primary splenocytes [61] . The effect of JNK on tonicity-dependent activation of NFAT5 is elusive and also least studied.…”

Section: Potential Clinical Significance Of This Reviewmentioning

confidence: 99%

“…Subsequent studies indicate that PKA contributes to tonicity-dependent activation of NFAT5 by suppressing the negative effect of GSK-3β on the transcription factor through increasing the inhibitory phosphorylation of GSK-3β at serine 9 [81] . PKA has also been suggested to contribute to tonicity-dependent activation of NFAT5 in the primary splenocytes, based on the inhibitory effect of H89 [61] . H89…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

“…SB203580, its analogs, p38α dominant negative mutant or siRNAs uniformly inhibits hypertonicity-induced NFAT5 transcriptional activity [53][54][55][56][57][58][59][60][61][62][63] . Because p38α is also called p38, it has been often concluded that p38 signals hypertonicityinduced activation of NFAT5.…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

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How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

Zhou

2016

WJN

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NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to, activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifically signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to maintain robustness against hypertonic or hypotonic stress. Core tip: NFAT5 is critical for kidney functions. Its disregulation results in or is associated with the renal diseases and disorders. More than a dozen of kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. The present review is focused on how these kinases regulate NFAT5 activity under the context of hypertonicity or hypotonicity. Understanding these regulatory mechanisms will have therapeutic implications. A precedent example is that recognition of the cyclosporine immunosuppressive effect resulted from inhibition of the phosphatase calcineurin-dependent activation of NFAT1 allows combination use of cyclosporine with other mechanistically different immunosuppressants to improve their therapeutic efficacy and reduce their side effects.Zhou X. How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5? World J Nephrol 2016; 5(1): 20-32 Available from:

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Section: Potential Clinical Significance Of This Reviewmentioning

confidence: 99%

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

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How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

Zhou

2016

WJN

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“…It has been suggested that the slightly hypertonic milieu of the thymus could be harmful for NFAT5-deficient thymocytes (24), but it is unclear whether thymic tonicity can activate NFAT5 (25). Nfat5 fl/fl, Lck-Cre mice had normally isotonic plasma, and their DN3, DN4, and DP thymocytes expressed normal levels of the osmostress-inducible, NFAT5-dependent genes Akr1b3 and Slc5a3 (SI Appendix, Fig.…”

Section: Nfat5 Has Different Effects On Thymocyte Proliferation and Smentioning

confidence: 99%

“…Whereas the thymocyte and T-lymphocyte deficiency of NFAT5-null mice can be explained by their systemic hypernatremia (21, 22), mice expressing a T-lymphocyte-restricted dominant negative NFAT5 transgene were shown to have reduced thymic cellularity and peripheral T lymphopenia (23). Because the tonicity of the thymus is not high enough to activate NFAT5 (21,24,25), this suggests an osmostress-independent role of NFAT5 in thymocyte development. Here we describe that NFAT5 expression is regulated by the IκB kinase β (IKKβ) pathway in thymocytes and acts as a survival factor downstream from the pre-TCR, independent of its osmoprotective function.…”

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NFAT5 induction by the pre–T-cell receptor serves as a selective survival signal in T-lymphocyte development

Berga-Bolaños

Alberdi

Buxadé

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKβ regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αβ thymocytes and the transition from the β-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in β-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKβ/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.T-cell development | gene expression E arly thymocyte differentiation proceeds through doublenegative (DN; CD4 − and CD8 − ) steps (1, 2) from the DN1 to the early DN3 (E-DN3) stages until cells express a recombined β allele of the T-cell receptor (TCR), which, together with the nonvariant pre-Tα and the CD3 complex, constitute a functional pre-TCR (3). The pre-TCR marks the commitment to the αβ T-cell lineage and controls the β-selection checkpoint in a ligandindependent manner by regulating allelic exclusion of the TCRβ locus, proliferation, survival, and differentiation of thymocytes, all of which are required for progression of DN3 to double-positive (DP; CD4 + and CD8 + ) cells (4-6). At the DP stage, thymocytes recombine the TCRα and express the mature TCRαβ complex, which interacts with self-peptide-MHC complexes of thymic antigen-presenting cells (7). This interaction determines the positive and negative selection of DP thymocytes from which CD4 + or CD8 + single-positive (SP) cells emerge. SP cells then migrate to peripheral organs to populate them with mature T lymphocytes.Despite knowledge accumulated on signaling pathways activated by the pre-TCR, less is known about the specialization of transcription factors downstream from this receptor and the genes they control (8). The Rel-like transcription factors NF-κB and the calcineurin-dependent NFATc proteins regulate thymocyte development downstream of the pre-TCR (9-16). Thymocytes also express the calcineurin-independent NFAT protein NFAT5, which has hybrid features of both NF-κB and NFATc proteins (17,18). NFAT5 protects cells from osmotic stress (19), and NFAT5-deficient mice present severe atrophy of the renal medulla, systemic hypernatremia, and a reduced thymocyte compartment and mature T-cell lymphopenia (20,21). Whereas the thymocyte and T-lymphocyte deficiency of NFAT5-null mice can be explained by their systemic hypernatremia (21, 22), mice expressing a T-lymphocyte-restricted dominant negat...

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Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

et al. 2011

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Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR < 0.05). Of these differentially expressed genes, the promoter regions of the human homologs were searched for common TF binding sites (TFBS). Eighteen TFBS were overrepresented >two-fold (p < 0.01) in upregulated and 13 in downregulated genes. Left ventricular nuclear protein extracts were assayed for DNA-binding activity by protein/DNA array. Out of 345 DNA probes, 30 showed signal intensity changes >two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-011-0229-1) contains supplementary material, which is available to authorized users.

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Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

Cited by 36 publications

References 47 publications

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

NFAT5 induction by the pre–T-cell receptor serves as a selective survival signal in T-lymphocyte development

Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

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