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J. Biol. Chem., Vol. 277, Issue 37, 33950-33956, September 13, 2002
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From the Departments of Medicine and Pathology and the Molecular
Biology Program, University of Colorado Health Sciences Center,
Denver, Colorado 80262
Although most studies of progesterone receptors
(PR) and their two isoforms, PR-A and PR-B, focus on transcriptional
stimulation, the receptors exhibit important inhibitory properties.
Autoinhibition refers to an inhibitory function
located in the PR N terminus, whose deletion increases transcriptional
activity at least 6-10-fold. Transrepression refers to the
ability of PR-A to suppress the transcriptional activity of PR-B and
other nuclear receptors, including estrogen receptors.
Self-squelching refers to the observation in transient
transfection assays that increasing receptor concentrations paradoxically decrease transcriptional activity. Using a series of
N-terminal deletion mutants constructed in both PR isoforms, we have
mapped their autoinhibitory and transrepressor activities to a small
ubiquitin-like modifier (SUMO-1) protein consensus-binding motif,
387IKEE, located in the N terminus upstream of AF1.
Self-squelching does not involve this site. SUMO-1 binds PR covalently
at 387IKEE, but only if the C-terminal, liganded,
hormone-binding domain is also present. A single point K388R mutation
within the 387IKEE motif in either PR-A or PR-B leads to a
loss of autoinhibitory and transrepressor functions of the liganded,
full-length receptors. We conclude that autoinhibition and
transrepression involve N-terminal sumoylation combined with
intramolecular N/C-terminal communication.
The Inhibitory Function in Human Progesterone Receptor N
Termini Binds SUMO-1 Protein to Regulate Autoinhibition and
Transrepression*
,
*
This work was supported by Grants DK48238 and CA26869 from
the National Institutes of Health, by The Avon Foundation, and by funds
from the National Foundation for Cancer Research (to K. B. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Medicine/Endocrinology, Box B151, School of Medicine, University of
Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. Tel.: 303-315-8850; Fax: 303-315-4525; E-mail:
hany.abdel-hafiz@uchsc.edu.
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