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Molecular and Cellular Biology, April 2007, p. 2919-2933, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.00936-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

c-Jun Homodimers Can Function as a Context-Specific Coactivator

Benoit Grondin,¹ Martin Lefrancois,¹ Mathieu Tremblay,¹ Marianne Saint-Denis,¹ André Haman,¹ Kazuo Waga,³ André Bédard,^4, Daniel G. Tenen,⁵ and Trang Hoang^1,2*

Institute of Research in Immunology and Cancer,¹ Departments of Pharmacology, Biochemistry, and Molecular Biology, University of Montreal, Montréal, Québec, Canada H3C 3J7,² Department of Hematology, Dokkyo University School of Medicine, Tochigi 321-0293, Japan,³ Department of Biology, York University, North York, Ontario, Canada M3J 1P3,⁴ Harvard Institutes of Medicine and Harvard Stem Cell institute, Harvard Medical School, Boston, Massachusetts 02115⁵

Received 26 May 2006/ Returned for modification 25 July 2006/ Accepted 16 January 2007

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-1ß (IL-1ß) promoter in the absence of direct DNA binding via protein-protein interactions with DNA-anchored PU.1 and CCAAT/enhancer-binding protein ß (C/EBPß). Unexpectedly, the interaction interface with PU.1 and C/EBPß 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-1ß locus is occupied by PU.1 and C/EBPß 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.

Published ahead of print on 5 February 2007.

Present address: Department of Biology, McMaster University, 1280 Main St., West Hamilton, Ontario L8S 4K1, Canada.

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