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Molecular and Cellular Biology, August 2000, p. 6040-6050, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Common Motif within the Negative Regulatory Regions of Multiple Factors Inhibits Their Transcriptional Synergy

Jorge A. Iñiguez-Lluhí1,* and David Pearce2

Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632,1 and Departments of Cellular and Molecular Pharmacology and Medicine, University of California, San Francisco, San Francisco, California 94143-04502

Received 27 March 2000/Returned for modification 5 May 2000/Accepted 23 May 2000

DNA regulatory elements frequently harbor multiple recognition sites for several transcriptional activators. The response mounted from such compound response elements is often more pronounced than the simple sum of effects observed at single binding sites. The determinants of such transcriptional synergy and its control, however, are poorly understood. Through a genetic approach, we have uncovered a novel protein motif that limits the transcriptional synergy of multiple DNA-binding regulators. Disruption of these conserved synergy control motifs (SC motifs) selectively increases activity at compound, but not single, response elements. Although isolated SC motifs do not regulate transcription when tethered to DNA, their transfer to an activator lacking them is sufficient to impose limits on synergy. Mechanistic analysis of the two SC motifs found in the glucocorticoid receptor N-terminal region reveals that they function irrespective of the arrangement of the receptor binding sites or their distance from the transcription start site. Proper function, however, requires the receptor's ligand-binding domain and an engaged dimer interface. Notably, the motifs are not functional in yeast and do not alter the effect of p160 coactivators, suggesting that they require other nonconserved components to operate. Many activators across multiple classes harbor seemingly unrelated negative regulatory regions. The presence of SC motifs within them, however, suggests a common function and identifies SC motifs as critical elements of a general mechanism to modulate higher-order interactions among transcriptional regulators.

* Corresponding author. Mailing address: Department of Pharmacology, The University of Michigan Medical School, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0632. Phone: (734) 515-6565. Fax: (734) 763-4450. E-mail: iniguez{at}umich.edu.

Molecular and Cellular Biology, August 2000, p. 6040-6050, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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