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1 (Estrogen Related Receptor -1)
Division of Immunology (D.Z., K.M.Q., C.Y., S.C.)
Beckman Research Institute of the City of Hope
Duarte,
California 91010
Department of Biology (S.Y.L., B.P.)
Dalhousie University Halifax, Nova Scotia B3H 4J1, Canada
PNRC (proline-rich nuclear receptor coregulatory
protein) was identified using bovine SF1 (steroidogenic factor 1) as
the bait in a yeast two-hybrid screening of a human mammary gland cDNA
expression library. PNRC is unique in that it has a molecular
mass of 35 kDa, significantly smaller than most of the
coregulatory proteins reported so far, and it is proline-rich. PNRC’s
nuclear localization was demonstrated by immunofluorescence and Western
blot analyses. In the yeast two-hybrid assays, PNRC interacted with the
orphan receptors SF1 and ERR
1 in a ligand-independent manner. PNRC
was also found to interact with the ligand-binding domains of
all the nuclear receptors tested including estrogen receptor (ER),
androgen receptor (AR), glucocorticoid receptor (GR), progesterone
receptor (PR), thyroid hormone receptor (TR), retinoic acid receptor
(RAR), and retinoid X receptor (RXR) in a ligand-dependent manner.
Functional AF2 domain is required for nuclear receptors to bind to
PNRC. Furthermore, in vitro
glutathione-S-transferase pull-down assay was performed to
demonstrate a direct contact between PNRC and nuclear receptors such as
SF1. Coimmunoprecipitation experiment using Hela cells that express
PNRC and ER was performed to confirm the interaction of PNRC and
nuclear receptors in vivo in a ligand-dependent manner.
PNRC was found to function as a coactivator to enhance the
transcriptional activation mediated by SF1, ERR1 (estrogen related
receptor -1), PR, and TR. By examining a series of deletion mutants
of PNRC using the yeast two-hybrid assay, a 23-amino acid (aa) sequence
in the carboxy-terminal region, aa 278–300, was shown to be critical
and sufficient for the interaction with nuclear receptors. This region
is proline rich and contains a SH3-binding motif,
S-D-P-P-S-P-S. Results from the mutagenesis
study demonstrated that the two conserved proline (P)
residues in this motif are crucial for PNRC to interact with the
nuclear receptors. The exact 23-amino acid sequence was also found in
another protein isolated from the same yeast two-hybrid screening
study. These two proteins belong to a new family of nuclear receptor
coregulatory proteins.
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