Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun.
Cooperation between nuclear factor of activated T cells (NFAT) and AP-1 (Fos-Jun) proteins on composite NFAT-AP-1 DNA elements constitutes a powerful mechanism for signal integration of the calcium and protein kinase C/Ras pathways in the regulation of gene expression. Here we report that NFAT can induce expression of certain genes in T cells without the need for cooperative recruitment of Fos and Jun. Using NFAT1 mutant proteins that are unable to interact with Fos-Jun dimers but are unaffected in DNA binding or transcriptional activity, we show that expression of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-4, MIP1alpha and Fas ligand mRNAs is absolutely dependent on cooperation between NFAT and Fos-Jun; in contrast, NFAT induces tumor necrosis factor alpha (TNFalpha) mRNA and IL-13 promoter activity without any necessity to recruit Fos and Jun. Furthermore, we show that NFAT-Fos-Jun cooperation is also essential to elicit the NFAT-dependent program of activation-induced cell death. Our results support the hypothesis that even in a single cell type, NFAT activation can evoke two distinct biological programs of gene expression, dependent or independent of NFAT-AP-1 cooperation.
Macián
F
F
Department of Pathology, Harvard Medical School and the Center for Blood Research, 200 Longwood Avenue, Boston, MA 02115, USA.
García-Rodríguez
C
C
Rao
A
A
D000595:Amino Acid Sequence; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017354:Point Mutation; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors