title: NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription.
abstract: Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the -45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the -45 NFAT site was replaced by either an NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the -45 NFAT site by NFATc2, where it acts as a co-activator for IL-2 transcription.
authors.affiliation: University of Colorado, Department of Chemistry and Biochemistry, Boulder, CO 80303-0596, United States.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Walters
authors.forename: Linda F
authors.initials: LF
authors.lastname: Drullinger
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Kugel
authors.forename: James A
authors.initials: JA
authors.lastname: Goodrich
mesh_terms: D001665:Binding Sites / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D007376:Interleukin-2; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D008156:Luciferases