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J Biol Chem, Vol. 274, Issue 32, 22618-22626, August 6, 1999
From the Department of Pathology, University of Southern
California, Los Angeles, California 90033
Orphan nuclear receptors share sequence homology
with members of the nuclear receptor superfamily, but ligands are
unknown or unnecessary. A novel orphan receptor, estrogen
receptor-related protein 3 (ERR3), was identified by yeast two-hybrid
screening, using the transcriptional coactivator glucocorticoid
receptor interacting protein 1 (GRIP1) as bait. The putative
full-length mouse ERR3 contains 458 amino acids and is closely related
to two known orphan receptors ERR1 and ERR2. All the ERR family members share an almost identical DNA-binding domain, which has 68% amino acid
identity with that of estrogen receptor. ERR3 bound specifically to an
estrogen response element and activated reporter genes controlled by
estrogen response elements, both in yeast and in mammalian cells, in
the absence of any added ligand. A conserved AF-2 activation domain
located in the hormone-binding domain of ERR3 was primarily responsible
for transcriptional activation. The ERR3 AF-2 domain bound GRIP1 in a
ligand-independent manner both in vitro and in vivo, through the LXXLL motifs of GRIP1, and GRIP1
functioned as a transcriptional coactivator for ERR3 in both yeast and
mammalian cells. Expression of ERR3 in adult mouse was restricted;
highest expression was observed in heart, kidney, and brain. In the
mouse embryo no expression was observed at day 7, and highest
expression occurred around the 11-15 day stages. Although ERR3 is much
more closely related to ERR2 than to ERR1, the expression pattern for ERR3 was similar to that of ERR1 and distinct from that for ERR2, suggesting a unique role for ERR3 in development.
Hormone-independent Transcriptional Activation and Coactivator
Binding by Novel Orphan Nuclear Receptor ERR3
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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