Bidirectional regulation of tonicity-responsive enhancer binding protein in response to changes in tonicity

Woo, Seung Kyoon; Dahl, Stephen C.; Handler, Jerome S.; Kwon, H. Moo

doi:10.1152/ajprenal.2000.278.6.f1006

Cited by 138 publications

(180 citation statements)

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“…The TonE consensus sequence is recognized by the recently identified transcription factor TonE-binding protein (TonEBP) (27,36). In agreement with the present data, activation of TonEBP in response to a hypertonic challenge requires Ͼ10 h (27), whereas a hypotonic challenge rapidly decreases TonEBP activity (27,38).…”

Section: Aqp2 Promotersupporting

confidence: 89%

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Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

Storm

Klussmann

Geelhaar

et al. 2003

American Journal of Physiology-Renal Physiology

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. Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells. Am J Physiol Renal Physiol 284: F189-F198, 2003. First published August 13, 2002; 10.1152/ajprenal.00245.2002The water permeability of the renal collecting duct is regulated by the insertion of aquaporin-2 (AQP2) into the apical plasma membrane of epithelial (principal) cells. Using primary cultured epithelial cells from the inner medulla of rat kidney (IMCD cells), we show that osmolality and solute composition are potent regulators of AQP2 mRNA and protein synthesis, as well as the classical cAMP-dependent pathway, but do not affect the arginine vasopressin-induced AQP2 shuttle. In the presence of the cAMP analog dibutyryl cAMP (DBcAMP, 500 M), NaCl and sorbitol, but not urea, evoked a robust increase of AQP2 expression in IMCD cells, with NaCl being far more potent than sorbitol. cAMP-responsive elementbinding protein phosphorylation increased with DBcAMP concentrations but was not altered by changes in osmolality. In the rat and human AQP2 promoter, we identified a putative tonicity-responsive element. We conclude that, in addition to the arginine vasopressin/cAMP-signaling cascade, a further pathway activated by elevated effective osmolality (tonicity) is crucial for the expression of AQP2 in IMCD cells, and we suggest that the effect is mediated via the tonicityresponsive element. osmolality; aquaporin-2; kidney; gene regulation; toxicity responsive enhancer THE WATER CHANNEL aquaporin-2 (AQP2), expressed in epithelial (principal) cells of renal collecting ducts, is required for the vasopressin-dependent concentration of urine (7). AQP2 abundance increases from the kidney cortex to the inner region of the kidney medulla (29), as does osmolality. The water permeability of the inner medullary collecting duct (IMCD) is rapidly regulated (within minutes) by the antidiuretic hormone arginine vasopressin (AVP), which binds to heptahelical vasopressin V 2 receptors (V 2 R), located mainly in the basolateral plasma membrane of principal cells. Activation of the V 2 R causes stimulation of adenylyl cyclase via the G protein G S , leading to elevation of cAMP. The subsequent activation of protein kinase A (PKA) initiates the translocation of AQP2-bearing vesicles from the cytosol to the plasma membrane, in which AQP2 is inserted by an exocytosis-like process (short-term regulation) (D. Lorenz, A. Krylov, V. Hagen, J. Zipper, W. Rosenthal, P. Pohl, and K. Maric, unpublished observations; 30). In addition, the signaling cascade described above governs the expression of AQP2 (long-term regulation) by PKA-mediated phosphorylation of the transcription factor cAMP-responsive element (CRE)-binding protein (CREB) (13,16). Given the fact that AQP2 biosynthesis is usually shut off shortly after IMCD cells are established in primary culture (10), most studies on AQP2 long-term regulation have been performed using animal models (29, 37). We recently established primary cultured IMCD cells as a model system (17,18,21,22). Thes...

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Section: Aqp2 Promotersupporting

confidence: 89%

“…7). Nuclear abundance and overall expression of TonEBP are rapidly decreased by hypotonic challenge (27,38). As reported for AQP2 (24,37), dehydration increases the sodium-myo-inositol cotransporter mRNA expression in rat renal medulla, whereas water loading decreases it.…”

Section: Discussionsupporting

confidence: 59%

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

Storm

Klussmann

Geelhaar

et al. 2003

American Journal of Physiology-Renal Physiology

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“…However, we cannot exclude that, Regulation of NFAT5 by ddx5/ddx17 S Germann et al in some cellular contexts, the NFAT5 mRNA bearing exon 5 may escape NMD. However, many reports have indicated that NFAT5 protein level is tightly regulated, particularly during differentiation and in response to hyper-osmotic stresses (Woo et al, 2000;Ferraris et al, 2002). It has been shown that NFAT5 protein level is regulated by several mechanisms involving protein stability and miRNA-mediated mRNA silencing (Dahl et al, 2001;Irarrazabal et al, 2010;Levy et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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“…NFAT5 plays an important role in allowing cell to adapt to hypertonic environment. In Madin-Darby canine kidney cells, hypertonicity increases the abundance of NFAT5, contributing to increased transcription of downstream osmoprotective genes [19]. Hypertonicity stabilizes NFAT5 mRNA which depends on the presence of the 5'-untranslated region (UTR) [13].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of NFAT5 by RNA interference reduces monoclonal antibody productivity of hybridoma cells

Zou

Xie

2007

Cell Res

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Hybridoma cells display an increase in antibody productivity following exposure to hypertonic conditions. However, the underlying mechanism is not well understood. In the present study, we hypothesize that the nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP) functions to increase the antibody productivity of hybridoma cells. NFAT5 is an osmosensitive mammalian transcription factor. However, its ubiquitous expression in various organs that are not bathed in hypertonic milieu suggests that NFAT5 may also regulate cell growth and function under isotonic conditions. In this study, we examined the expression of NFAT5 in hybridoma cells by Western blot analysis, and found that it increased significantly in hypertonic medium. To further define the function of NFAT5 in hybridoma cells, RNA interference technique was used to downregulate the expression of NFAT5 in SGB-8 cells (a hybridoma cell line). In isotonic medium, antibody productivity of hybridoma cells was reduced by downregulation of NFAT5 while cell proliferation was not influenced. The results presented here demonstrate that NFAT5 not only plays an important role in osmotic stress response pathway in hybridoma cells but also is essential for optimal antibody productivity.

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Bidirectional regulation of tonicity-responsive enhancer binding protein in response to changes in tonicity

Cited by 138 publications

References 44 publications

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Downregulation of NFAT5 by RNA interference reduces monoclonal antibody productivity of hybridoma cells

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