Disease relevance of NFATC4

• Although the strength of the associations was rather weak, these observations raise the hypothesis that the G160A polymorphism of the NFATC4 gene plays a role in the development of human cardiac hypertrophy [1].
• Knockdown of endogenous NFAT3 reduced the growth of human breast cancer ZR75-1 cells in a ligand-independent manner [2].
• Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease [3].
• Previously, we showed that activation of the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo [4].
• Nfatc2(-/-) Nfatc4(-/-) mice are also protected from diet-induced obesity [5].

High impact information on NFATC4

• We show that NFATc4 is specifically expressed in estrogen receptor positive breast cancer cells and inhibits their motility by downregulating the expression of LCN2 [6]
• We find that mice with disruptions of both NFATc4 and the related NFATc3 genes die around E11 with generalized defects in vessel assembly as well as excessive and disorganized growth of vessels into the neural tube and somites [7].
• NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription [3].
• We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus [3].
• We have isolated two additional members of this gene family, NF-AT3 and NF-AT4, which encode proteins 65% identical to the other NF-AT proteins within the Rel domain [8].
• Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation [9].

Chemical compound and disease context of NFATC4

• NFAT3 belongs to the NFAT family of transcription factors playing important roles in the development of several organ systems and was found to act as a transcriptional coactivator of estrogen receptors (ERalpha and ERbeta) in breast cancer cells [10].

Biological context of NFATC4

• For the G160A polymorphism in NFATC4, genotype frequencies were compared between patients with dilated cardiomyopathy and controls obtained from the CARDIGENE Study. Allele A carriers were less frequent in the patient than in the control group (P=0.04) [1].
• NFAT3 bound specifically to the ERbeta region containing the activation function-1 domain, a ligand-independent transactivation domain [2].
• Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases [11].
• Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice [5].
• In contrast, deprivation of serum and K(+), which leads to neuronal apoptosis, triggered NFAT3 nuclear export [12].

Anatomical context of NFATC4

• NFAT3 was expressed differentially in many breast cancer cell lines and overexpressed in a subset of breast cancer patients [2].
• Stable expression of Ala(168,170) NFATc4, but not of wild-type NFATc4, in NIH 3T3 cells promotes adipocyte formation under differentiation conditions [11].
• Removal of the putative nuclear factor of activated T-cells (NFATs) binding site increased the promoter activity, and overexpression of NFATc4 reduced the promoter activity [13].
• The occurrence of NFATc4 in spinal cord was demonstrated with RT-PCR and immunocytochemistry [14].
• Translocation of NFAT was confirmed by Western blots, with NFAT3 the prominent isoform in pulmonary artery [15].

Associations of NFATC4 with chemical compounds

• A Gly/Ala substitution at position 160 of the NFATC4 protein (G160A) was associated with left ventricular mass and wall thickness (P=0.02 and 0.006, respectively, GA+AA vs GG), the minor allele (Ala) being associated with lower mean values of these parameters [1].
• NFAT3 increased binding of ERalpha to the estrogen-responsive element and was recruited to endogenous estrogen-responsive promoters [2].
• We demonstrate here that two transactivation domains, located at the NH(2) and COOH termini of NFATc4, are critical for interacting with CBP [16].
• Conversely, mutation of the KIX or CH3 domain prevents CBP-mediated potentiation of NFATc4 transcription activation [16].
• Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NFkappaB-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells [17].

Physical interactions of NFATC4

• NFAT3 interacted with ERalpha and ERbeta both in vitro and in mammalian cells in a ligand-independent fashion [2].

Regulatory relationships of NFATC4

• The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-alpha transcription [18].
• Replacement of Ser168 and Ser170, the amino acid residues on which NFAT3 can be phosphorylated, with Ala did not change the ability of NFAT3 to inhibit the transcriptional activity of ERalpha and ERbeta [10].
• The involvement of Rho-kinase in PE- and 20-HETE-induced NFAT3 translocation in pulmonary artery suggests a level of control not previously recognized in smooth muscle [15].

Other interactions of NFATC4

• We used a yeast two-hybrid system and identified NFAT3 as a novel ERbeta-binding protein [2].
• Taken together, these results suggest that NFAT3 may play important roles in ER signaling and represent a novel target for breast cancer therapy [2].
• Calcineurin, a heterodimeric protein composed of a catalytic and a regulatory subunit, activates the nuclear factor NFATC4 which after translocation to the nucleus associates with the transcription factor GATA4 to activate several cardiac genes involved in hypertrophic response [1].
• Treatment of granule neurons with Li(+), an inhibitor of the NFAT export kinase GSK3, prevented the nuclear export of NFAT3 and increased granule cell survival even under pro-apoptotic conditions [12].
• In macrophage-like cells in culture, NFATc1 through NFATc4 are expressed at similar low levels [19].

Analytical, diagnostic and therapeutic context of NFATC4

• In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT-3 in homogenates within nuclear extracts [20].

References