c-Jun homodimers can function as a context-specific coactivator.
Transcription factors can function as DNA-binding-specific activators or as coactivators. c-Jun drives gene expression via binding to AP-1 sequences or as a cofactor for PU.1 in macrophages. c-Jun heterodimers bind AP-1 sequences with higher affinity than homodimers, but how c-Jun works as a coactivator is unknown. Here, we provide in vitro and in vivo evidence that c-Jun homodimers are recruited to the interleukin-1beta (IL-1beta) promoter in the absence of direct DNA binding via protein-protein interactions with DNA-anchored PU.1 and CCAAT/enhancer-binding protein beta (C/EBPbeta). Unexpectedly, the interaction interface with PU.1 and C/EBPbeta involves four of the residues within the basic domain of c-Jun that contact DNA, indicating that the capacities of c-Jun to function as a coactivator or as a DNA-bound transcription factor are mutually exclusive. Our observations indicate that the IL-1beta locus is occupied by PU.1 and C/EBPbeta and poised for expression and that c-Jun enhances transcription by facilitating a rate-limiting step, the assembly of the RNA polymerase II preinitiation complex, with minimal effect on the local chromatin status. We propose that the basic domain of other transcription factors may also be redirected from a DNA interaction mode to a protein-protein interaction mode and that this switch represents a novel mechanism regulating gene expression profiles.
Grondin
Benoit
B
Institute of Research in Immunology and Cancer, University of Montreal, P.O. Box 6128, Downtown station, Montréal, Québec.
Lefrancois
Martin
M
Tremblay
Mathieu
M
Saint-Denis
Marianne
M
Haman
André
A
Waga
Kazuo
K
Bédard
André
A
Tenen
Daniel G
DG
Hoang
Trang
T
D000595:Amino Acid Sequence; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015870:Gene Expression; D053583:Interleukin-1beta / Q000235:genetics; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D013698:Templates, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D022782:CCAAT-Enhancer-Binding Protein-beta; D004247:DNA; D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012319:RNA Polymerase II; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1