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Molecular and Cellular Biology, August 2000, p. 6040-6050, Vol. 20, No. 16
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.
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
*
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.
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