Signal Integration by Transcription-factor Assemblies: Interactions of NF-AT1 and AP-1 on the IL-2 Promoter

The logic of transcriptional control in a differentiatedcell is embodied in the molecular interactions and eventsthat direct assembly and modification of a set of transcription factors, coactivators, and other proteins, on acomplex set of regulatory sites. In the specific case of theinterleukin-2 (IL-2) promoter, nearly 300 bp encompassseveral sites for the nuclear factor of activated T cells(NF-AT), two likely sites for Rel-family dimers, an octamer site (adjacent to one of the NF-AT sites), and presumably others yet to be characterized (Jain et al. 1995;Serfling et al. 1995). The distal antigen-recognition response element (ARRE2) encodes a small part of theoverall program that determines transcription of IL-2mRNA (Rao et al. 1997). It contains sites for NF-AT andfor AP-1 (a heterodimer of Fos and Jun family members),which bind cooperatively and which together contributeto activation. In effect, the structure of this element andthe interactions among the NF-AT and AP-1 componentsrepresent the following "computation": if (NF-AT is inthe nucleus) and if (Jun is activated) and if (Fos is present), then (deliver a positive output to the transcriptionalapparatus). In making this simple analogy, we assumethat nuclear localization of NF-AT, activation of Jun, andsynthesis of Fos are sufficient to lead to cooperative DNAbinding. In fact, execution of the routine just outlinedmay require previous execution of other routines, such asunblocking of the ARRE2 site by histone modification.We believe, however, that some important aspects of thetranscriptional "computer hardware" are contained in thecomplex of NF-AT, Jun, Fos, and the ARRE2 DNA,which we describe here in some detail...