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Gene Review

Nfat5  -  nuclear factor of activated T cells 5

Mus musculus

Synonyms: AI225870, B130038B15Rik, CAG-8, CAG80, NF-AT5, ...
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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


Anatomical context of Nfat5


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


  1. Osmotic response element-binding protein (OREBP) is an essential regulator of the urine concentrating mechanism. Lam, A.K., Ko, B.C., Tam, S., Morris, R., Yang, J.Y., Chung, S.K., Chung, S.S. J. Biol. Chem. (2004) [Pubmed]
  2. NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment. Go, W.Y., Liu, X., Roti, M.A., Liu, F., Ho, S.N. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. López-Rodríguez, C., Antos, C.L., Shelton, J.M., Richardson, J.A., Lin, F., Novobrantseva, T.I., Bronson, R.T., Igarashi, P., Rao, A., Olson, E.N. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. Complete cDNA sequence, expression, alternative splicing, and genomic organization of the mouse Nfat5 gene. Dalski, A., Hebinck, A., Winking, H., Butzmann, U., Schwinger, E., Zühlke, C.h. Cytogenet. Genome Res. (2002) [Pubmed]
  5. TonEBP/NFAT5 stimulates transcription of HSP70 in response to hypertonicity. Woo, S.K., Lee, S.D., Na, K.Y., Park, W.K., Kwon, H.M. Mol. Cell. Biol. (2002) [Pubmed]
  6. Transgenic mice expressing dominant-negative osmotic-response element-binding protein (OREBP) in lens exhibit fiber cell elongation defect associated with increased DNA breaks. Wang, Y., Ko, B.C., Yang, J.Y., Lam, T.T., Jiang, Z., Zhang, J., Chung, S.K., Chung, S.S. J. Biol. Chem. (2005) [Pubmed]
  7. Mouse TonEBP-NFAT5: expression in early development and alternative splicing. Maouyo, D., Kim, J.Y., Lee, S.D., Wu, Y., Woo, S.K., Kwon, H.M. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  8. Sequential expression of NKCC2, TonEBP, aldose reductase, and urea transporter-A in developing mouse kidney. Lee, H.W., Kim, W.Y., Song, H.K., Yang, C.W., Han, K.H., Kwon, H.M., Kim, J. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  9. Urea inhibits hypertonicity-inducible TonEBP expression and action. Tian, W., Cohen, D.M. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  10. Rottlerin inhibits tonicity-dependent expression and action of TonEBP in a PKCdelta-independent fashion. Zhao, H., Tian, W., Cohen, D.M. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  11. Role of integrin alpha1beta1 in the regulation of renal medullary osmolyte concentration. Moeckel, G.W., Zhang, L., Chen, X., Rossini, M., Zent, R., Pozzi, A. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  12. Activation of TonEBP by calcium controls {beta}1,3-glucuronosyltransferase-I expression, a key regulator of glycosaminoglycan synthesis in cells of the intervertebral disc. Hiyama, A., Gajghate, S., Sakai, D., Mochida, J., Shapiro, I.M., Risbud, M.V. J. Biol. Chem. (2009) [Pubmed]
  13. NFAT5 binds to the TNF promoter distinctly from NFATp, c, 3 and 4, and activates TNF transcription during hypertonic stress alone. Esensten, J.H., Tsytsykova, A.V., Lopez-Rodriguez, C., Ligeiro, F.A., Rao, A., Goldfeld, A.E. Nucleic Acids Res. (2005) [Pubmed]
  14. Regulation of expression of the stress response gene, Osp94: identification of the tonicity response element and intracellular signalling pathways. Kojima, R., Randall, J.D., Ito, E., Manshio, H., Suzuki, Y., Gullans, S.R. Biochem. J. (2004) [Pubmed]
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