Disease relevance of NFATC2

• Structure of NFAT1 bound as a dimer to the HIV-1 LTR kappa B element [1].
• Here we report a crystal structure of NFAT1 bound cooperatively as a dimer to the highly conserved kappa B site from the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) [1].
• Cord blood (CB) cells are now an important source of stem cells for bone marrow reconstitution as a result of the decreased risk of graft-versus-host disease that was attributed to previously reported absent or diminished nuclear factor of activated T (NFAT) cell 1 expression by CB T cells [2].
• This toxicity might be absent in antagonists that target NFAT directly [3].
• The expression patterns of the principal components of calcineurin/NFAT signaling pathway in normal human skin and psoriasis were determined by immunohistochemistry [4].

High impact information on NFATC2

• Recent findings in B lymphocytes have clearly illustrated that these external inputs affect the magnitude and duration of the intracellular calcium response, which in turn contributes to differential triggering of the transcriptional regulators NF kappa B, JNK, NFAT, and ERK [5].
• NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells [6].
• As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much attention [6].
• The activity of NFAT proteins is tightly regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a primary target for inhibition by cyclosporin A and FK506 [6].
• NFAT proteins, which are expressed in most immune-system cells, play a pivotal role in the transcription of cytokine genes and other genes critical for the immune response [6].

Chemical compound and disease context of NFATC2

• Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A [4].
• Within the HIV long terminal repeat (LTR), two purine-rich domains between nucleotides -283 and -195 have homology to a regulatory region found in the interleukin 2 promoter, which binds NFAT and other cellular factors [7].
• In six of seven pancreatic cancer cell lines and pancreatic tumor specimens with 20q13 amplifications, the novel candidate gene NFAT C2, which plays a role in the activation of cytokines, was amplified [8].
• The immunosuppressive drug cyclosporin A (CsA) inhibits NFAT activity and thus represents a potential treatment for HIV-1 infection [9].
• We found that selective NFAT inhibition during phenylephrine stimulation inhibited hypertrophy but resulted in increased cardiomyocyte apoptosis [10].

Biological context of NFATC2

• The nuclear factor of the activated T cell (NFAT) family of transcription factors regulates cytokine gene expression by binding to the promoter/enhancer regions of antigen-responsive genes, usually in cooperation with heterologous DNA-binding partners [11].
• The other protein, NF-ATp, is highly homologous to NF-ATc over a limited domain which shows similarity to the Dorsal/Rel family, but has a wider tissue distribution [12].
• We have defined the mechanisms of transactivation by NFAT1 [13].
• The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family [13].
• These results implicate NFAT as an important mediator of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-protein interaction with other transcription factors [14].

Anatomical context of NFATC2

• Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system [15].
• NK cell NFAT is present in the cytosol of nonstimulated cells, migrates to the nucleus upon stimulation, and can associate with AP-1 [16].
• Stimulation of NK cells with CD16 ligands induces NFAT-like DNA binding activity in the nuclear extracts from these cells, as detected in electrophoretic mobility shift assays [16].
• In A20 B cells, the TNF-alpha gene is not regulated by NFATp bound to the kappa 3 element [17].
• DNA-binding of silencer and activator from T-helper, and NFAT-1 from Jurkat cells, requires the same three G residues, but cross-linking analyses show differences in their constituent subunits [18].

Associations of NFATC2 with chemical compounds

• Furthermore, pharmacological studies demonstrate that the drug cyclosporin A inhibits both NFAT activation and IL-2 expression [19].
• In DNA binding assays, both PMA plus anti-CD28 and PMA plus ionomycin resulted in nuclear NFAT [20].
• Vav also did not stimulate detectable Ca(2+) mobilization and nuclear translocation of NFATc or NFATp [21].
• Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1 [22].
• Furthermore, mutation or deletion of NFAT binding sites in the human COX-2 promoter greatly diminished its induction by phorbol 12-myristate 13-acetate/calcium ionophore A23187 [23].

Physical interactions of NFATC2

• It has been shown that nuclear factor of activated T cells (NFAT) interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism of activation of MEF2D by calcineurin [14].
• Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin alpha6beta4 expressing cells [24].
• Previously, we have shown that NFATc.beta, an isoform of NFATc, is different from NFATp in both DNA binding and transactivation of the TNF-alpha promoter [25].
• As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter [26].
• Competition with an AP-1 motif or with anti-Jun and anti-Fos antibodies abolished binding to the NFAT motif in both T and B cells, indicating that Jun and Fos are critical for NFAT complex formation in both cell types [27].

Enzymatic interactions of NFATC2

• We show here that the peptidyl prolyl cis-trans isomerase Pin1 interacts specifically with the phosphorylated form of NFAT [28].

Regulatory relationships of NFATC2

• PKCzeta cooperates with calcium ionophore and with NFAT1 or NFAT2 proteins to enhance transcriptional activation of a NFAT reporter construct [29].
• Functionally, transcriptional reporter assays and RNA interference ATRAP experiments demonstrated that ATRAP knockdown increased nuclear factor of activated T cells (NFAT) activity [30].
• BACKGROUND: The nuclear factor of activated T cells (NFAT) family of transcription factors plays a key role in rapidly inducing IL4 gene expression in effector T cells [31].
• Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression [32].
• In conclusion, our results indicate that NFAT activation by stimuli acting in a more distal fashion from the TCR-mediated signaling pathway can be down-regulated by CD45 and that this CD45-dependent regulation in turn affects HIV-1 long terminal repeat activation [33].
• The promoter/enhancer activity of the NFAT-binding site in the TNF-alpha gene was up-regulated by NFATc2 but not by NFATc1, whereas both NFATs associated similarly with this region [34].

Other interactions of NFATC2

• We report here that NFATp synergizes with MEF2D to recruit the coactivator p300 for the transcription of Nur77 [14].
• Comparison to other NFAT structures, including NFAT5 and the NFAT1-Fos-Jun-ARRE2 complex, reveals that NFAT1 adopts different conformations and its protein surfaces mediate distinct protein-protein interactions in the context of different DNA sites [1].
• Properties of transcription factors regulating interleukin-2 gene transcription through the NFAT binding site in untreated or drug-treated naive and memory T-helper cells [18].
• Electromobility shift assays showed that NFAT1 and activator protein-1 are both translocated to the nucleus following bpV treatment [35].
• The NFAT-dependent promoters from the IL-2 and TNF-alpha genes were also more potently activated by PMA/Iono in J45.01 cells [33].

Analytical, diagnostic and therapeutic context of NFATC2

• 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 [22].
• 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 [20].
• Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation [30].
• METHODS: Intracellular NFAT protein was identified by using 2-color flow cytometry; gene expression was done with RT-PCR [31].
• RESULTS: Both peripheral blood and bronchoalveolar lavage fluid eosinophils expressed NFATp and NFATc protein [36].

References