Partners in transcription: NFAT and AP-1.
Combinatorial regulation is a powerful mechanism that enables tight control of gene expression, via integration of multiple signaling pathways that induce different transcription factors required for enhanceosome assembly. The four calcium-regulated transcription factors of the NFAT family act synergistically with AP-1 (Fos/Jun) proteins on composite DNA elements which contain adjacent NFAT and AP-1 binding sites, where they form highly stable ternary complexes to regulate the expression of diverse inducible genes. Concomitant induction of NFAT and AP-1 requires concerted activation of two different signaling pathways: calcium/calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and protein kinase C (PKC)/Ras, which promotes the synthesis, phosphorylation and activation of members of the Fos and Jun families of transcription factors. A fifth member of the NFAT family, NFAT5, controls the cellular response to osmotic stress, by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP-1. Pharmacological interference with theNFAT:AP-1 interaction may be useful in selective manipulation of the immune response. Balanced activation of NFAT and AP-1 is known to be required for productive immune responses, but the role of NFAT:AP-1 interactions in other cell types and biological processes remains to be understood.
Macián
F
F
Department of Pathology, Harvard Medical School and the Center for Blood Research, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA.
López-Rodríguez
C
C
Rao
A
A
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D046911:Macromolecular Substances; D008958:Models, Molecular; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020218:Response Elements; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation
D016207:Cytokines; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004247:DNA