The role of TonEBP in regulation of AAD expression and dopamine production in renal proximal tubule cells upon hypertonic challenge

Hsin, Yi-Hong; Tang, Cheng-Hao; Lai, Hsing-Tzu; Lee, Tsung‐Han

doi:10.1016/j.bbrc.2011.09.128

Cited by 12 publications

(11 citation statements)

References 28 publications

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“… 66 , 70 Interestingly, a recent study suggests that NFAT5 could participate in DA synthesis and secretion in renal proximal tubule cells. 71 If NFAT5 is involved in DA neurotransmission in the brain, genetic variants within this gene may predispose to cocaine dependence through changes in DA activity. This would be in agreement with ‘the reward deficiency syndrome' hypothesis, which postulates that hypodopaminergic activity predisposes to cocaine addiction.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

et al. 2015

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Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case–control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3′-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

et al. 2015

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“…This finding could be supported by the fact that the activity of TonEBP was regulated mainly at the level of nucleocytoplasmic distribution, 27 and the activated TonEBP could further enhance the mRNA expression of the downstream genes. 28 When translocated into the nucleus, the detailed mechanisms of TonEBP on the transcriptional activity of TauT were further explored.…”

Section: Discussionmentioning

confidence: 99%

TonEBP modulates the protective effect of taurine in ischemia-induced cytotoxicity in cardiomyocytes

et al. 2015

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Taurine, which is found at high concentration in the heart, exerts several protective actions on myocardium. Physically, the high level of taurine in heart is maintained by a taurine transporter (TauT), the expression of which is suppressed under ischemic insult. Although taurine supplementation upregulates TauT expression, elevates the intracellular taurine content and ameliorates the ischemic injury of cardiomyocytes (CMs), little is known about the regulatory mechanisms of taurine governing TauT expression under ischemia. In this study, we describe the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway involved in the taurine-regulated TauT expression in ischemic CMs. Taurine inhibited the ubiquitin-dependent proteasomal degradation of TonEBP, promoted the translocation of TonEBP into the nucleus, enhanced TauT promoter activity and finally upregulated TauT expression in CMs. In addition, we observed that TonEBP had an anti-apoptotic and anti-oxidative role in CMs under ischemia. Moreover, the protective effects of taurine on myocardial ischemia were TonEBP dependent. Collectively, our findings suggest that TonEBP is a core molecule in the protective mechanism of taurine in CMs under ischemic insult.

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“…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%

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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The role of TonEBP in regulation of AAD expression and dopamine production in renal proximal tubule cells upon hypertonic challenge

Cited by 12 publications

References 28 publications

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

TonEBP modulates the protective effect of taurine in ischemia-induced cytotoxicity in cardiomyocytes

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

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