The long-term objectives of this project are to understand the mechanisms of inducible gene transcription in activated T lymphocytes. The current focus is the role of the bZIP family of transcription factors, particularly AP-1 (Fos/Jun) family members, in cytokine gene induction. Members of the bZIP family of transcription factors, whose DNA-binding motif is comprised of a basic region adjacent to a leucine zipper, are known to cooperate with several different classes of transcription factors to regulate inducible and constitutive gene transcription. Among the transcription factors known to associate with AP-1 proteins is the inducible, cyclosporin-sensitive transcription factor NFAT (nuclear factor of activated T cells), which is essential for Interleukin 2 (il2) gene transcription. (NFAT contains a constitutively expressed about 120 kDa phosphoprotein which we have termed NF-ATp, which associates with Fos and Jun proteins in the nucleus of activated T cells. Antisera and cDNA clones for NFATp that have been generated in this laboratory will be used to investigate systematically the interactions between NFATp and bZIP proteins.
The specific aims of this proposal are: I. To investigate the physical interactions between bZIP proteins and NFATp. The residues of Fos/Jun proteins required for interaction with NFATp, and the regions of NFATp required for DNA binding, dimerisation and interaction with Fos and Jun proteins, will be identified; whether NFATp and Fos/Jun proteins associate in the absence of DNA, and whether other bZIP proteins interact with NFATp, will be determined; and the DNA binding of NFATp in the absence and presence of bZIP proteins will be evaluated. II. To investigate the functional interactions between bZIP proteins and NFATp. The regions of NFATp required for transcriptional activity will be identified; and the mechanism by which bZIP proteins influence the transcriptional activity of NFATp will be determined. III. T investigate the functions of NFATp and bZIP proteins in cytokine gene induciton. The function of NFATp in vivo will be evaluated by targeted mutagenesis; the functions of different NFATp isoforms in IL2, TNFalpha, and IL4 gene transcription will be determined; and the potential involvement of bZIP proteins in regulating TNFalpha, and IL4 gene transcription will be determined; and the potential involvement of bZIP proteins in regulating TNFalpha gene transcription will be examined.
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