NF-AT

from Wikipedia, the free encyclopedia
NF-AT
Identifier
Gene name (s) NFATC1 , NFATC2 , NFATC3 , NFATC4 , NFAT5
Occurrence
Parent taxon Vertebrates

NF-AT or NFAT ( nuclear factor of activated T-cells ) are transcription factors in lymphocytes of vertebrates which, when activated, bind to a promoter in the cell nucleus and thus start the gene expression of cytokines such as interleukin-2 ( IL-2 ). NF-AT have different characteristic binding sites: a DNA binding domain for transcription and two different calcineurin binding domains for activation by calcineurin .

In humans, these are the proteins NF-ATC1 (NF-AT2), NF-ATC2 (NF-AT1), NF-ATC3 (NF-AT4), NF-ATC4 (NF-AT3) and NF-AT5 . The NF-ATCx are cytosolic, while NF-AT5 is located exclusively in the cell nucleus. The NF-ATCx together form a complex (NFATC) in the cell nucleus, which is necessary for the transcription function. However, the subunits also have isolated functions.

activation

The NF-AT are phosphorylated in the cytosol . In this state they are inactive.

After activation of the antigen receptor of his lymphocytes, a signal cascade occurs. The calcium concentration in the cytosol increases. These calcium ions, together with calmodulin, form a complex that binds calcineurin (a phosphatase ). This activates the catalytic subunit of calcineurin. Calcineurin dephosphorylates the phosphorylated nuclear localization signal of NF-AT. As a result, the NF-AT are transported through nuclear pores into the cell nucleus, where they first form the NFATC complex. This binds to NF-AT elements, specific binding sites for individual NF-AT on the DNA, and thus activates the transcription of z. B. Interleukin-2 (IL-2).

After the IL-2 gene expression has taken place, IL-2 binds autocrine to an IL-2 receptor of the T lymphocytes . This activates the T lymphocyte and stimulates cell proliferation .

inhibition

Inhibition of NF-AT is possible on the one hand by inhibiting calcineurin or calmodulin, which prevents activation, or by a number of relatively small, mostly bicyclic or tricyclic organic substances that inhibit the binding of calcineurin to NF-AT. The high immunosuppressive effect of the inhibition of NF-AT by cyclosporin A and tacrolimus ( FK 506 ), which are used in organ transplants , is of clinical interest . Both immunosuppressants block the activation of calcineurin.

Individual evidence

  1. ↑ Homologues at OMA
  2. ↑ FJ Garcia-Cozar, H. Okamura, JF Aramburu, KTY Shaw, L. Pelletier, R. Showalter, E. Villafranca and A. Rao: Two-site Interaction of Nuclear Factor of Activated T Cells with Activated Calcineurin J. Biol. Chem. 1998 273: 23877-23883.
  3. ^ A b Wissenschaft-Online-Lexika: Entry on NF-AT in the Lexikon der Biologie, accessed on December 10, 2009
  4. ↑ MHA Roehrl, JY Wang and G. Wagner: Discovery of small molecule inhibitor of the NFAT-calcineurin interaction by Competitive high-throughput Fluorescence Polarization screening. Biochemistry, 2004, 43 (51), pp. 16067-16075