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

• NFATc3-null mice also demonstrated attenuated pressure overload- and angiotensin II-induced cardiac hypertrophy [8].

Biological context of Nfatc3

• For example, CD4(+) T cells isolated from NFATx-disrupted mice do not show any modulation in cytokine gene expression, perhaps because other family members compensate for its absence [9].
• It has been reported that both NFAT1 and NFATx are required to maintain the homeostasis of the immune system [9].
• Calcineurin and NFAT4 induce chondrogenesis [10].
• NFATc3 is the product of a gene on murine chromosome 8 that is not linked to the other NFATc genes [11].
• We also found that lack of NFATc2 and NFATc3 obviates the necessity for engagement of CD28 on naïve cells and controls the time required to reach the first cell division upon activation [7].

Anatomical context of Nfatc3

• To further understand the diverse roles of antigen receptor signaling throughout T cell development, we have identified a new NFATc family member, NFATc3, that is expressed at highest levels in the thymus [11].
• The calcineurin substrate, NFAT4, also induced chondrogenesis and chondrocyte gene expression [10].
• Importantly, Kv currents did not change after MI in ventricular myocytes from NFATc3 knockout mice [3].
• NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells [12].
• Whereas the loss of NFATc4 did not compromise the ability of the myocardium to undergo hypertrophic growth, NFATc3-null mice demonstrated a significant reduction in calcineurin transgene-induced cardiac hypertrophy at 19 days, 26 days, 6 weeks, 8 weeks, and 10 weeks of age [8].

Associations of Nfatc3 with chemical compounds

• Consistent with this hypothesis, we found that in vivo administration of angiotensin II-activated calcineurin/NFATc3 signaling in arterial smooth muscle [13].
• However, vasoconstrictors (e.g. uridine triphosphate (UTP)) and growth factors, which elevate intracellular Ca2+ and engage multiple intracellular signaling pathways, induce a robust increase in smooth muscle nuclear NFATc3 [14].
• Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension [13].
• In contrast, activation of GCA by atrial natriuretic peptide (10(-6) mol/L) inhibited phenylephrine (10(-6) mol/L)-stimulated nuclear translocation of NFATc3 [15].

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].

References