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Gene Review

Nfatc3  -  nuclear factor of activated T cells,...

Mus musculus

Synonyms: C80703, D8Ertd281e, NF-AT4, NF-ATc3, NFAT4, ...
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Disease relevance of Nfatc3

  • The provirus insertions are positioned close to the Nfatc3 promoter or a putative polyadenylated RNA (polyA) region [1].
  • Here, we show that mice lacking both NFATp and NFAT4 develop a profound lymphoproliferative disorder likely due to a lowered threshold for TCR signaling coupled with increased resistance to apoptosis secondary to defective FasL expression [2].
  • Furthermore, we demonstrate that NFATc3-deficient mice infected with SL3-3 develop T-cell lymphomas faster and with higher frequencies than wild-type mice or NFATc2-deficient mice [1].
  • These results identify NFATc3 as a tumor suppressor for the development of murine T-cell lymphomas induced by the retrovirus SL3-3 [1].
  • NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction [3].
  • Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation [4].

High impact information on Nfatc3

  • The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 (DKO) [5].
  • Here we report that NFAT4, in contrast to NFATp and NFATc, is preferentially expressed in DP thymocytes [6].
  • The transcription factor NFAT4 is involved in the generation and survival of T cells [6].
  • Further, mice lacking NFAT4 have impaired production of Bcl-2 mRNA and protein [6].
  • We found that naïve T(H) precursors that are doubly deficient in NFATc2 and NFATc3 intrinsically differentiate into TH(2)-secreting cells, even in the absence of interleukin 4 (IL-4) production [7].

Chemical compound and disease context of Nfatc3


Biological context of Nfatc3


Anatomical context of Nfatc3


Associations of Nfatc3 with chemical compounds


Regulatory relationships of Nfatc3

  • In naive CD4(+) T cells, NFATx up-regulated the expression of several cytokine genes and activation markers and suppressed the expression of CD154 [9].
  • In contrast, NFATx suppressed Th2 cytokine genes such as IL-4 and IL-5 in Th2 cells [9].
  • NFATc3 activates NFAT site-dependent transcription when overexpressed, yet exhibits a pattern of DNA site specificity distinct from other NFATc proteins [11].
  • Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export [16].
  • Here we show that depolarizing stimuli that normally fail to induce NFATc3 nuclear accumulation in arterial smooth muscle effectively induce nuclear accumulation under conditions in which Crm-1-dependent or JNK2-mediated nuclear export processes are disrupted [14].

Other interactions of Nfatc3

  • A mechanism for the compromised immune response is suggested by the observation that CnA beta(-/-) T cells are defective in stimulation-induced NFATc1, NFATc2, and NFATc3 activation [17].
  • EMSA competition and supershift analyses reveal the formation of multiple DNA-protein complexes at these sites that include Yin Yang 1, Oct1, and NFAT-4 [18].
  • Our results suggest that NFATx exerts this function by inhibiting the expression of some critical immunoregulatory genes [9].
  • A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus [1].
  • Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2(-/-) mice [16].


  1. A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Glud, S.Z., Sørensen, A.B., Andrulis, M., Wang, B., Kondo, E., Jessen, R., Krenacs, L., Stelkovics, E., Wabl, M., Serfling, E., Palmetshofer, A., Pedersen, F.S. Blood (2005) [Pubmed]
  2. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Ranger, A.M., Oukka, M., Rengarajan, J., Glimcher, L.H. Immunity (1998) [Pubmed]
  3. NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction. Rossow, C.F., Minami, E., Chase, E.G., Murry, C.E., Santana, L.F. Circ. Res. (2004) [Pubmed]
  4. NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. de Frutos, S., Spangler, R., Alò, D., Bosc, L.V. J. Biol. Chem. (2007) [Pubmed]
  5. Sequential involvement of NFAT and Egr transcription factors in FasL regulation. Rengarajan, J., Mittelstadt, P.R., Mages, H.W., Gerth, A.J., Kroczek, R.A., Ashwell, J.D., Glimcher, L.H. Immunity (2000) [Pubmed]
  6. The transcription factor NFAT4 is involved in the generation and survival of T cells. Oukka, M., Ho, I.C., de la Brousse, F.C., Hoey, T., Grusby, M.J., Glimcher, L.H. Immunity (1998) [Pubmed]
  7. NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naïve T(H)cells. Rengarajan, J., Tang, B., Glimcher, L.H. Nat. Immunol. (2002) [Pubmed]
  8. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Wilkins, B.J., De Windt, L.J., Bueno, O.F., Braz, J.C., Glascock, B.J., Kimball, T.F., Molkentin, J.D. Mol. Cell. Biol. (2002) [Pubmed]
  9. Role of NFATx (NFAT4/NFATc3) in expression of immunoregulatory genes in murine peripheral CD4+ T cells. Chen, J., Amasaki, Y., Kamogawa, Y., Nagoya, M., Arai, N., Arai, K., Miyatake, S. J. Immunol. (2003) [Pubmed]
  10. Calcineurin and NFAT4 induce chondrogenesis. Tomita, M., Reinhold, M.I., Molkentin, J.D., Naski, M.C. J. Biol. Chem. (2002) [Pubmed]
  11. NFATc3, a lymphoid-specific NFATc family member that is calcium-regulated and exhibits distinct DNA binding specificity. Ho, S.N., Thomas, D.J., Timmerman, L.A., Li, X., Francke, U., Crabtree, G.R. J. Biol. Chem. (1995) [Pubmed]
  12. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. Bopp, T., Palmetshofer, A., Serfling, E., Heib, V., Schmitt, S., Richter, C., Klein, M., Schild, H., Schmitt, E., Stassen, M. J. Exp. Med. (2005) [Pubmed]
  13. Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension. Nieves-Cintrón, M., Amberg, G.C., Nichols, C.B., Molkentin, J.D., Santana, L.F. J. Biol. Chem. (2007) [Pubmed]
  14. Constitutively elevated nuclear export activity opposes Ca2+-dependent NFATc3 nuclear accumulation in vascular smooth muscle: role of JNK2 and Crm-1. Gomez, M.F., Bosc, L.V., Stevenson, A.S., Wilkerson, M.K., Hill-Eubanks, D.C., Nelson, M.T. J. Biol. Chem. (2003) [Pubmed]
  15. Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Tokudome, T., Horio, T., Kishimoto, I., Soeki, T., Mori, K., Kawano, Y., Kohno, M., Garbers, D.L., Nakao, K., Kangawa, K. Circulation (2005) [Pubmed]
  16. Intraluminal pressure is a stimulus for NFATc3 nuclear accumulation: role of calcium, endothelium-derived nitric oxide, and cGMP-dependent protein kinase. Gonzalez Bosc, L.V., Wilkerson, M.K., Bradley, K.N., Eckman, D.M., Hill-Eubanks, D.C., Nelson, M.T. J. Biol. Chem. (2004) [Pubmed]
  17. Defective T cell development and function in calcineurin A beta -deficient mice. Bueno, O.F., Brandt, E.B., Rothenberg, M.E., Molkentin, J.D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Yin Yang 1, Oct1, and NFAT-4 form repeating, cyclosporin-sensitive regulatory modules within the murine CD21 intronic control region. Zabel, M.D., Wheeler, W., Weis, J.J., Weis, J.H. J. Immunol. (2002) [Pubmed]
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