nuclear factor of activated T-cells, cytoplasmic 1; NF-ATc1; NFAT transcription complex cytosolic component; NF-ATc; NFATc (NFATC1, NFAT2, NFATC)
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Function
- role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription
- also controls gene expression in embryonic cardiac cells
- may regulate not only the activation & proliferation, but also differentiation & programmed death of T-lymphocytes as well as other lymphoid & non-lymphoid cells
- phosphorylated by NFATC-kinase
- dephosphorylated by calcineurin
- member of the multicomponent NFATC transcription complex
- binds to DNA as monomer
Structure
- Rel similarity domain (RSD) allows DNA-binding & cooperative interactions with AP1 factors
- the N-terminal transactivation domain (TAD-A) binds to & is activated by Cbp/p300
- dephosphorylated form contains two unmasked nuclear localization signals (NLS), which allow translocation of the protein to the nucleus
- isoform C has a C-terminal part with an additional trans-activation domain, TAD-B, which acts as a transcriptional activator
- isoform B has a shorter C-terminal part without complete TAD-B which acts as a transcriptional repressor
- contains 1 RHD (Rel-like) domain
Compartment
- cytoplasm. nucleus
- cytoplasmic for the phosphorylated form
- nuclear after activation that is controlled by calcineurin-mediated dephosphorylation
- rapid nuclear exit of NFATC is thought to be one mechanism by which cells distinguish between sustained & transient Ca+2 signals
- the subcellular localization of NFATC plays a key role in regulation of gene transcription
Alternative splicing
Alternative initiation; Named isoforms=9 potency in activation of gene transcription: isoforms C > A > B; isoforms A, B & C have alpha & beta forms
Expression
- expressed in T-cells within thymus, peripheral blood & spleen
- isoform A is preferentially expressed in effector T-cells (thymus & peripheral blood)
- isoforms B & C are preferentially expressed in naive T-cells (spleen)
- isoforms B is expressed in naive T-cells after first antigen exposure
- isoform A is expressed in effector T-cells after second antigen exposure
- only isoform A is inducibly expressed in T lymphocytes upon activation of the T-cell receptor (TCR) complex
- induced after co-addition of phorbol 12-myristate 13-acetate (PMA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) & ionomycin; further addition of cyclosporin A seems to inhibit induction