Disease relevance of NFATC3

• NFAT4 Is Required for JC Virus Infection of Glial Cells [1].
• We report here that NFAT4 is expressed in U373 astrocytoma cells and in primary cultures of astrocytes [2].
• Of the 25, NFAT4 and the oncogene ets-2 bind to the common motif AAGGAG found in the HIV-1 LTR and IL-2 probes [3].

High impact information on NFATC3

• Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1 [4].
• MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha [4].
• CKIalpha thus acts to establish an intramolecular masking of the nuclear location signal on NF-AT4, while MEKK1 augments this mechanism, and may further provide a link to signal transduction pathways regulating NF-AT4 [4].
• Casein kinase Ialpha directly binds and phosphorylates NF-AT4, resulting in the inhibiton of NF-AT4 nuclear translocation [4].
• Mutational removal of the JNK phosphorylation sites caused constitutive nuclear localization of NFAT4 [5].

Biological context of NFATC3

• Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR [6].
• The expression pattern of NFATx, together with its functional activity, strongly suggests that NFATx plays a role in the regulation of gene expression in T cells and immature thymocytes [7].
• Here, we report that deletion of the critical serine-rich motifs of NFATx leads to a conformation that efficiently exposes the nuclear localization signal and that has stronger transcription activity compared with the fully activated wild-type protein in the presence of the nuclear export sequence [8].
• A constitutively nuclear form of NFATx shows efficient transactivation activity and induces differentiation of CD4(+)CD8(+) T cells [8].
• This also suggests that the regulation of the transactivation domain by phosphorylation observed in NFAT1 may not contribute significantly to the transcription activity of NFATx [8].

Anatomical context of NFATC3

• NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus [7].
• NFATx mRNA is preferentially and remarkably found in the thymus and at lower levels in peripheral blood leukocytes [7].
• Likewise, NFAT2 mRNA was constitutively expressed in basophils, and message for NFAT4 was seen in 3 of 5 preparations, whereas that for NFAT1 was found in only 1 of 5 preparations [9].
• Calcineurin and NFATc3 proteins were detected in the embryonic and adult mouse lung epithelium, and the mRNA expression profiles of the NFATs were similar in immortalized mouse lung epithelial cells and alveolar epithelial type II cells [10].
• Activity- and calcineurin-independent nuclear shuttling of NFATc1, but not NFATc3, in adult skeletal muscle fibers [11].

Associations of NFATC3 with chemical compounds

• Moreover, this DNA binding was inhibited by cyclosporin A, indicating that NFATx nuclear translocation was regulated by the calcineurin phosphatase in DP thymocytes [12].
• In resting fibers, the nuclear export inhibitor leptomycin B caused nuclear accumulation of NFATc1 (but not of isoform NFATc3) and formation of NFATc1 intranuclear bodies independent of calcineurin [11].
• NFAT4 is expressed in primary astrocytes and activated by glutamate [2].
• Overexpression of human NFATc3 and NFATc4 greatly increased the acetylcholinesterase promoter activity in HeLa cells treated with A23187 [13].
• Consistent with this hypothesis, we found that in vivo administration of angiotensin II-activated calcineurin/NFATc3 signaling in arterial smooth muscle [14].

Other interactions of NFATC3

• 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 [15].
• Likewise, NF-AT1 mRNA and NF-AT4 mRNA have been detected in resting eosinophils, and their levels can be significantly up-regulated by the Th2-associated cytokines IL-4 and IL-5 [16].
• The effect of clenbuterol and pST on potential signaling pathways in vivo was also assessed by monitoring protein phosphatase 2B (calcineurin), NFATc3, calpain 3, IkappaB alpha, and NFkappaB by quantitative immunoblotting [17].

Analytical, diagnostic and therapeutic context of NFATC3

• Luciferase reporter assays and chromatin immunoprecipitation assays revealed that NFAT4 directly bound the JCV promoter during infection and was important for the activation of both early and late transcription [1].
• Using electrophoretic mobility shift assay, we observed stimulation-dependent NFAT-DNA binding in CD4(+)CD8(+) thymocytes, which was largely dependent on NFATx protein [18].
• Immunofluorescence assay showed that both mNFATx1 and m delta NFATx introduced into COS-7 cells localized predominantly to the cytoplasm, but did translocate to the nucleus, either by cotransfection with an active form of calcineurin or wild-type calcineurin followed by stimulation with calcium ionophore [19].
• Calcineurin-dependent nuclear translocation of a murine transcription factor NFATx: molecular cloning and functional characterization [19].
• Northern blot analysis showed mNFATx1 to be predominantly expressed in the thymus. mNFATx1, but not m delta NFATx, produced in COS-7 cells, bound to all NFAT-binding sites of the interleukin (IL)-2 and IL-4 promoters tested [19].

References