Disease relevance of NFATC1

• We propose that the MCP-1-induced TRAP(+)/CTR(+) multinuclear cells represent an arrested stage in osteoclast differentiation, after NFATc1 induction and cellular fusion but prior to the development of bone resorption activity [1].
• The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells [2].
• Mice deficient for the transcription factor NFATc1 fail to form pulmonary and aortic valves, a defect reminiscent of some types of congenital human heart disease [3].
• With the exception of the transcription factor NFATC1, which shows a tendency towards gene dosage compensation (the expression pattern correlates with IgA deficiency), all of the other genes were expressed at a level proportional to their gene copy number [4].
• Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway [5].
• In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites [6].

High impact information on NFATC1

• Sculpting heart valves with NFATc and VEGF [7].
• Calcium signaling activates the phosphatase calcineurin and induces movement of NFATc proteins into the nucleus, where they cooperate with other proteins to form complexes on DNA [8].
• Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter [9].
• T cells therefore can become competent for HIV-1 replication by control of regulated host factors such as the NFATc transcription factor [10].
• NFATc overcame a blockade at reverse transcription and permitted active HIV-1 replication [10].

Chemical compound and disease context of NFATC1

• MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase, NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption [1].

Biological context of NFATC1

• Additional size heterogeneity of both NFATc and NFATp results from phosphorylation [11].
• Although NFATc1 was strongly induced by MCP-1 and was observed in the nucleus, MCP-1 did not permit the formation of bone-resorbing osteoclasts, although these cells had the typical TRAP(+)/CTR(+) multinuclear phenotype of osteoclasts [1].
• Ablation of NFATc1 in mature osteoclasts did not prevent bone resorption activity, suggesting NFATc1 is involved in cell fusion events and not bone resorption [1].
• NFATc1 with AP-3 site binding specificity mediates gene expression of prostate-specific-membrane-antigen [12].
• T-cell receptor stimulation also induced a very rapid expression of c-jun, c-fos and NFATc1 (NFATc) genes, the gene products of which are involved in cytokine gene expression [13].

Anatomical context of NFATC1

• Using a panel of specific antisera in immunoprecipitation assays, we found that NFATp (135 kDa) is constitutively expressed in normal human T cells, while synthesis of NFATc (predominant form of 86 kDa) is induced by ionomycin treatment [11].
• Here we provide evidence that NFATc1 and NFATc2 are expressed in human colon carcinoma cell lines [14].
• RESULTS: Basophils constitutively expressed high levels of NFAT2 [15].
• CONCLUSIONS: The selective and specific expression of NFAT2 in basophils is unique among leukocytes [15].
• NF-ATc RNA expression is largely restricted to lymphoid tissues and is induced upon T-cell activation [16].

Associations of NFATC1 with chemical compounds

• NFATc1 directly induces the human beta3 integrin gene in osteoclast differentiation [17].
• Vav also did not stimulate detectable Ca(2+) mobilization and nuclear translocation of NFATc or NFATp [18].
• Importantly, both cyclosporin A and the calcineurin-specific peptide inhibitor reduced VEGF-induced human pulmonary valve endothelial cell proliferation, indicating a functional role for NFATc1 in endothelial growth [3].
• The amino acid sequence of NFATc.beta differs from that of NFATc. alpha in the first NH2-terminal 29 residues and contains an additional region of 142 residues at the COOH terminus [19].
• The rate of nuclear uptake of NFATc1 was 4.6 times lower in resting fibers exposed to leptomycin B than during electrical stimulation [20].

Physical interactions of NFATC1

• Electrophoretic mobility shift assays reveal that recombinant EGR-1 and NFATc bind independently to their target sites within the IL-2 promoter, and the presence of both sites on the same DNA molecule is required for EGR-1.NFATc.DNA complex formation [21].
• Although NF-ATp copurifies with NF-ATc, there is as yet no understanding of how NF-ATp is functioning in vivo [22].
• Although the overall fold of the NFATc DNA-binding domain is related to that of NF-kappaB p50 (refs 2, 3), the two proteins use significantly different strategies for DNA recognition [23].
• Using immunoprecipitation Western blotting, we showed that NFATc1 interacted with GATA-6 [24].

Regulatory relationships of NFATC1

• These results suggest VEGF-induced NFATc1 activation may be an important mechanism in cardiac valve maintenance and function by enhancing endothelial proliferation [3].
• PKCzeta cooperates with calcium ionophore and with NFAT1 or NFAT2 proteins to enhance transcriptional activation of a NFAT reporter construct [25].
• Peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits NFATc1 activity in T cells and cardiomyocytes, but it is not known if PPARgamma controls NFATc1 function in endothelial cells [26].
• Grb3-3 is up-regulated in HIV-1-infected T-cells and can potentiate cell activation through NFATc [27].
• A brief incubation with the T(H)2 cytokines IL-4 and IL-5 was sufficient to induce the nuclear translocation of NFATc [28].

Other interactions of NFATC1

• In contrast to ionomycin treatment, exposure of cells to phorbol myristate acetate (PMA) plus anti-CD28 did not induce NFATc, indicating that under these conditions, interleukin-2 synthesis by these cells is apparently independent of NFATc [11].
• NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells [3].
• Constitutive expression of DSCR-1 in endothelial cells markedly impaired NF-ATc nuclear localization, proliferation, and tube formation [29].
• The transcriptional synergy observed here for EGR-1 and NFATc explains how the abundant nuclear factor EGR-1 contributes to the expression of restrictively expressed genes [21].
• Lacritin targets downstream NFATC1 and mTOR [30].

Analytical, diagnostic and therapeutic context of NFATC1

• Surprisingly, the PMA-ionomycin-induced synthesis of NFATc that was detected by immunoprecipitation was not mirrored in the DNA binding assays: nearly all of the activity was due to NFATp [11].
• Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells [31].
• Using a combination of transient transfections, electrophoretic mobility shift assays, and chromatin immunoprecipitation, thrombin was shown to induce time-dependent coordinate binding of RelA and NFATc to a tandem NF-kappaB element in the upstream promoter region of vascular cell adhesion molecule-1 [32].
• Finally, NFATc1 was detected in the endothelium of human pulmonary valve leaflets by immunohistochemistry [3].
• RESULTS: Both peripheral blood and bronchoalveolar lavage fluid eosinophils expressed NFATp and NFATc protein [28].

References