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, a Third Member of the Estrogen Receptor-Related Receptor (ERR) Subfamily of Orphan Nuclear Receptors: Tissue-Specific Isoforms Are Expressed during Development and in the Adult
Department of Molecular Genetics (D.J.H., P.L.N., H.V.)
Novo Nordisk A/S Novo Allè, DK-2880
Bagsvaerd,
Denmark
ZymoGenetics Inc. (J.H.) Seattle, Washington
98102
The nuclear receptor protein superfamily is a
large group of transcription factors involved in many aspects of animal
development, tissue differentiation, and homeostasis in the higher
eukaryotes. A subfamily of receptors, ERR
and ß (estrogen
receptor-related receptor and ß), closely related to the ER, were
among the first orphan nuclear receptors identified. These receptors
can bind DNA as monomers and are thought to activate transcription
constitutively, unaffected by ß-estradiol. Studies of the expression
patterns of ERR and gene disruption experiments of ERRß indicate
that they play an important role in the development and differentiation
of specific tissues in the mouse. In this work we demonstrate the
existence in humans of a third member of this subfamily of receptors,
termed ERR
, which is highly expressed in a number of diverse fetal
and adult tissues including brain, kidney, pancreas, and placenta. The
ERR mRNA is highly alternatively spliced at the 5'-end, giving rise
to a number of tissue-specific RNA species, some of which code for
protein isoforms differing in the N-terminal region. Like ERR and
ß, ERR binds as a monomer to an ERRE. A GAL4-ERR fusion protein
activates transcription in a ligand-independent manner in transfected
HEK293 cells to a greater degree than either the GAL4-ERR or -ß
fusion proteins.
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