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Transcription factors of the NFAT family: regulation and function
1Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA. arao@cbr.med.harvard.edu
Abstract:
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. 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. 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. Calcineurin controls the translocation of NFAT proteins from the cytoplasm to the nucleus of activated cells by interacting with an N-terminal regulatory domain conserved in the NFAT family. The DNA-binding domains of NFAT proteins resemble those of Rel-family proteins, and Rel and NFAT proteins show some overlap in their ability to bind to certain regulatory elements in cytokine genes. 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. This review discusses recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation of NFAT proteins with other transcription factors to regulate the expression of inducible genes.
Insights
Nuclear factor of activated T cells (NFAT) proteins are key regulators of immune responses, controlled by calcineurin. This review covers NFAT diversity, regulation, and cooperation with other factors like AP-1 for gene expression.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Nuclear factor of activated T cells (NFAT) proteins are crucial transcription factors in immune cells.
- NFATs regulate genes essential for immune responses, including cytokine production.
- Their activity is modulated by calcineurin, a target of immunosuppressive drugs like cyclosporin A and FK506.
Purpose of the Study:
- To review recent advancements in understanding the NFAT family of transcription factors.
- To elucidate the regulatory mechanisms governing NFAT protein activity within cells.
- To explore the cooperative interactions of NFAT proteins with other transcription factors.
Main Methods:
- Literature review of recent data on NFAT.
- Analysis of NFAT protein regulation by calcineurin.
- Examination of NFAT interactions with Rel and AP-1 transcription factors.
Main Results:
- NFAT proteins are diverse and critical for immune cell gene transcription.
- Calcineurin tightly regulates NFAT translocation to the nucleus.
- NFAT proteins cooperate with AP-1 (Fos/Jun) and Rel-family proteins at composite regulatory sites.
Conclusions:
- NFAT transcription factors are central to immune system regulation.
- Understanding NFAT regulation and cooperation is vital for immune response research.
- NFATs, in conjunction with other factors, control inducible gene expression in immune cells.