Disease relevance of Nfat5

• Furthermore, the OREBPdn Tg mice developed progressive hydronephrosis soon after weaning, confirming the osmoprotective function of OREBP implicated by the in vitro experiments [1].

High impact information on Nfat5

• Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state [2].
• Nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation [2].
• The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5 [3].
• Here we report that NFAT5/TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity [2].
• Furthermore, hypertonicity-induced NFAT5/TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired [2].

Biological context of Nfat5

• Complete cDNA sequence, expression, alternative splicing, and genomic organization of the mouse Nfat5 gene [4].
• Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression [3].
• Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function [3].
• Partial loss of NFAT5/TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals [2].
• In the 5' flanking region of the HSP70-2 gene, there are three sites for TonEBP binding [5].

Anatomical context of Nfat5

• Recent studies suggest that OREBP also plays a role in water reabsorption in the kidney, T-cell proliferation, and embryonic development [6].
• To investigate the consequences of lacking OREBP activity, transgenic (Tg) mice that overexpress OREBPdn (dominant negative form of OREBP) specifically in the epithelial cells of the renal collecting tubules were generated [1].
• TonEBP is expressed in embryonic stem cells and throughout the stages of fetal development [7].
• TonEBP shifted from the cytoplasm to the nucleus in both vascular endothelial cells and MCD cells on P1, and its abundance increased gradually afterward [8].

Associations of Nfat5 with chemical compounds

• These data indicate that in addition to vasopressin, OREBP is another essential regulator of the urine concentrating mechanism [1].
• Taken together, these data 1) define a molecular mechanism of urea-mediated inhibition of tonicity-dependent signaling, and 2) underscore a role for TonEBP abundance in regulating TonE-mediated gene transcription [9].
• Consistent with these data, rottlerin inhibited tonicity-dependent expression of TonE binding protein (TonEBP) at the mRNA and protein levels [10].
• Another inhibitor of both novel and conventional PKC isoforms, GF-109203X, suppressed TonEBP-dependent transcription but failed to influence tonicity-inducible TonEBP expression [10].
• Utilizing inner medullary collecting duct cells, we demonstrate that the lack of integrin alpha1beta1 results in an impaired ability to induce the tonicity enhancer-binding protein TonEBP under hypertonic conditions [11].
• Inhibition of Cn following ionomycin treatment did not block GlcAT-I and tauT, a TonEBP-responsive reporter activity [12].

Physical interactions of Nfat5

• NFAT5 binds to the TNF promoter distinctly from NFATp, c, 3 and 4, and activates TNF transcription during hypertonic stress alone [13].

Other interactions of Nfat5

• Rottlerin inhibits tonicity-dependent expression and action of TonEBP in a PKCdelta-independent fashion [10].
• In this study, we show that NFAT5, the most recently described NFAT family member, binds to the TNF promoter in a manner distinct from other NFAT proteins and is a key mediator in the activation of TNF gene transcription during hypertonic stress alone [13].

Analytical, diagnostic and therapeutic context of Nfat5

• Electrophoretic gel mobility-shift assay showed a slowly migrating band binding to the Osp94-TonE probe, probably representing binding of TonEBP (TonE binding protein) to this enhancer element [14].

References