Nuclear receptor coactivator PRIP (peroxisome
proliferator-activated receptor (PPAR
)-interacting protein) and
PRIP-interacting protein with methyltransferase activity, designated
PIMT, appear to serve as linkers between cAMP response element-binding
protein-binding protein (CBP)/p300-anchored and PBP (PPAR
-binding
protein)-anchored coactivator complexes involved in the transcriptional
activity of nuclear receptors. To assess the biological significance of PRIP, we disrupted the PRIP gene in mice by homologous recombination. Mice nullizygous for PRIP died between embryonic day 11.5 and 12.5 (postcoitum) due in most part to defects in the development of
placenta, heart, liver, nervous system, and retardation of embryonic
growth. Transient transfection assays using fibroblasts isolated from
PRIP
/
embryos revealed a significant decrease in
the capacity for ligand-dependent transcriptional
activation of retinoid X receptor
and to a lesser effect on
PPAR
transcriptional activity. These observations indicate that PRIP
like PBP, CBP, and p300 is an essential and nonredundant coactivator.
 |
INTRODUCTION |
Our understanding of the mechanisms underlying transcriptional
activation by nuclear receptors has been advanced by the identification of nuclear receptor coactivators or coregulators that appear to influence embryonic development, cell proliferation, and
differentiation (1). These include
p160/SRC-11 (steroid receptor
coactivator-1) family with three members (SRC-1, TIF/GRIP1/SRC-2,
and pCIP/AIB1/ACTR/RAC3/TRAM1/SRC3) (2-6), CREB-binding protein
(CBP) (7), adenovirus E1A-binding protein p300 (8), peroxisome
proliferator-activated receptor-
(PPAR
)-binding protein (PBP)
(9), PPAR-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) (10-14) and
PPAR
coactivator-1 (PGC-1) (15), among others. Nuclear receptor
coactivators contain one or more conserved LXXLL (where L is
leucine and X any amino acid) signature motif, which has been found to be necessary and sufficient for
ligand-dependent interactions with the activation
function-2 domain present in the C-terminal hormone-binding region of
the nuclear receptors (1, 6). It is generally held that coactivators
play a central role in mediating nuclear receptor transcriptional
activity by functioning as at least two large multiprotein complexes
formed either sequentially or combinatorially (1). The first complex anchored by CBP/p300 and containing p/160 cofactors/SRC-1 cofactors exhibits histone acetyltransferase activity necessary for remodeling chromatin (1, 4, 7, 16), while the second multiprotein complex,
variously referred to as TRAP/DRIP/ARC mediator complex, which is
anchored by PBP (17-19), facilitates interaction with RNA polymerase
II complexes of the basal transcription machinery (1). Deletion of
CBP/p300 and PBP genes in the mouse results in embryonic lethality
around E11.5 days, indicating that disruption of these pivotal
anchoring coactivators affects the integrity of the cofactor complexes,
thus altering the function of many nuclear receptors and most likely of
other transcription factors (20-24).
Of interest is that the recently identified coactivator designated
PRIP/ASC2/RAP250/NRC/TRBP has also been shown to interact with several
nuclear receptors and with CBP/p300 and TRAP130 of the TRAP/DRIP/ARC
complex (10-14). Thus, PRIP appears to serve as a bridge between the
first complex anchored by CBP/p300 and the downstream TRAP/DRIP/ARC
mediator complex anchored by PBP. Furthermore, the recently isolated
PRIP-interacting protein with RNA methyltransferase activity,
designated PIMT (25), forms a complex with CBP, p300, and PBP (26),
further attesting to the possibility that two major multiprotein
cofactor complexes anchored by CBP/p300 and PBP, respectively, merge
into one megacomplex on DNA template (28). Since PRIP and PRIP-binding
protein PIMT appear to link the two cofactor complexes under in
vitro conditions, we have found it necessary to explore the
biological function of PRIP by generating mice with PRIP null
phenotype. We now demonstrate that PRIP is critical for the embryonic
development, since disruption of the PRIP gene in the mouse leads to
embryonic lethality around E11.5 to E12.5 days, implying that PRIP
(like CBP/p300 and PBP) is also critical for embryonic development and survival.
 |
MATERIALS AND METHODS |
Construction of Targeting Vector--
The genomic DNA fragment
containing the full-length PRIP gene was isolated from a mouse 129/Sv
P1 bacteriophage library (Genome Systems, St. Louis, MO), using
polymerase chain reaction with primers 5'-CAATGCAGCCTGTTCCTGT-3' and
5'-GCTGCTGCATCACCATGAAA-3' designed from mouse PRIP cDNA sequence
(10). A Cre-LoxP system was employed to delete exon 7 from the PRIP
gene. For this purpose, we constructed a triple-LoxP PRIP targeting
vector to generate a "floxed" mouse PRIP-targeted locus.
Generation of PRIP Null Mice--
The targeting vector was
linearized and electroporated into HM1 embryonic stem (ES) cells (28).
Transfected ES cells were selected in the medium with G418 (200 µg/ml), and the surviving colonies were screened for homologous
recombination by PCR with primers P1 5'-CCTACAGCTGCAAGCAAATC-3' and P2
5'-TATACGAAGTTATGCGGCCG-3'. ES cells with the appropriate PRIP floxed
targeted locus were further confirmed by Southern blot analysis (Fig.
1B), and the euploid selected ES cells were used for
injection into 3.5-day-old blastocysts derived from C57/B6 mouse by the
Northwestern University Targeted Mutagenesis Facility to generate
chimeric mice. Chimeric male mice were bred with wild type C57/B6
female to produce heterozygous mice, which were then crossed with
EIIa-Cre transgenic mice (29) to delete the DNA fragment between LoxP1
and LoxP3. EIIa-cre-mediated recombination occurs early in development
(2-8 cells), and mice carrying the allele with deletion were crossed
with wild type C57/B6 to achieve germ line transmission. The
heterozygous mice with expected deletion were interbred to generate
homozygous mutants.
Genotyping of Mice and Embryos--
DNA extracted from the tail
tips of mice and from the yolk sac of embryos was used for genotyping
by PCR. The mice carrying the recombination between LoxP1 and LoxP3 on
one allele were identified by PCR with primers P1/P2 and P3
(5'-CGGCCGCATAACTTCGTATA-3')/P4 (5'-TTCTTCTTCCGAGGCGGTTT-3'). Presence of P1/P2 product, while lacking P3/P4 amplification, indicated the deletion of PRIP gene on one
allele. The homozygosity for the deletion was detected by the absence
of exon 7 as ascertained by PCR with primers P5 5'-ACGGGCCACCAAATATGATG-3' and primer P4 (see above) (Fig.
1C).
RT-PCR and Western Blots--
For RT-PCR, total RNA was
extracted from embryos with TRIzol reagent (Invitrogen). Primers
5'-CCTACAGCTGCAAGCAAATC-3' and 5'-CGAACATGCTGCATGAGCTGA-3' were used to
amplify the region between exon 6 and exon 8 from the PRIP homozygous
mutant. To detect PRIP protein in embryos, whole cell lysates were
prepared from the embryos by homogenization and probed with anti-mouse
PRIP antiserum. The signal was detected by ECL detection system.
Histological Analysis and Immunohistochemistry--
Age-matched
embryos were fixed in paraformaldehyde or 10% of buffered formalin,
embedded in paraffin, serially sectioned at 5-µM
thickness in sagittal or transverse planes, and stained with hematoxylin and eosin. Immunohistochemical staining for the
localization of proliferating cell nuclear antigen (PCNA) was performed
using a standard avidin-biotin-peroxidase complex protocol as described previously (24). Giemsa stain was done using the standard protocol.
Isolation of Fibroblasts from Embryos and Transfection of Primary
Fibroblasts--
Mouse embryonic fibroblasts (MEF) were isolated from
E11.5 embryos and cultured in Dulbecco's modified Eagle's medium with 10% of fetal bovine serum as described (22). For transfection, 2 × 105 of MEFs were plated in six-well plates for overnight
culture. The transfections were carried out with LipofectAMINE-2000
Plus reagent according to manufacturer's instruction
(Invitrogen). Plasmids pCMV-PPAR
, PPRE-TK-LUC, pCMV-RXR,
RXRE-TK-LUC, pCMV-RAR, and RARE-TK-LUC were as described
previously (10, 25, 26).
-Galactosidase expression vector pCMV
was used as a cotransfectant, which served as control for transfection
efficiency. Cell extracts were prepared 36 h after transfection
and were assayed for luciferase and
-galactosidase activities.
 |
RESULTS |
Disruption of PRIP Gene in Mice--
We constructed a conditional
knock-out allele of PRIP by using the Cre/loxP recombination
system according to the strategy in Fig.
1A. To generate conventional
PRIP knock-out mice (in which the gene is permanently inactivated at
the germ cell stage), it was necessary to induce recombination between
loxP sites. To achieve heterozygosity, PRIP-targeted mice were bred
with homozygous Cre transgenic mouse line, EII-cre (29). The EII-cre
mice carry the Cre transgene under the control of the adenovirus EIIa
promoter and express Cre recombinase only in early mouse embryos (2-8
cell stage), and it induces the recombination between the two loxP sites with the same orientation (29). We detected the expected, all
types of recombinants among the offspring (29). The recombination between loxP1 and loxP3 resulted in the deletion of PRIP exon 7 and a
reading frameshift to generate a stop codon right after the fusion
between exon 6 and exon 8. The chimeras were crossed to wild type mice
to produce heterozygous mice carrying one recombinant PRIP allele, and
the homozygous mice were obtained from heterozygous mating. By
sequencing the RT-PCR products, exon 7 was not found in mRNA
transcribed from the recombinant PRIP allele, and the reading
frameshift was introduced by the deletion leading to a premature stop
codon (data not shown). As the result, only 488 amino acids at the N
terminus containing no LXXLL motif can possibly be
translated from the mRNA, but no PRIP protein was detected by
Western blot analysis (data not shown).

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Fig. 1.
Disruption of mouse PRIP gene.
A, schematic drawing of the targeting vector and the
recombinant alleles. Restriction sites SpeI (S),
HindIII (H), KpnI (K), and
the location of primers and probes used for ES cell screening and mouse
genotyping are indicated. Dashed lines show the regions of
homologous recombination between the vector and the endogenous gene.
B, Southern blot analysis of genomic DNAs from ES cells is
digested with SpeI and hybridized to show PRIP wild type
allele (6.3 kb) and recombinant allele (8.2 kb). C, DNA from
mice derived from heterozygous mating are screened by PCR with primers
P4/P5 to detect homozygous deletion of exon 7 (lane
4).
|
|
Embryonic Lethality and Growth Retardation of PRIP Null
Mice--
Among 26 new-born pups, and 54 mice that were 3 weeks old
generated from intercrosses between heterozygous PRIP mutant mice, no
homozygous mutants were detected. Genotyping the embryos at different
stages of gestation showed that no PRIP null embryos survived beyond
E13.5 (13.5 days postcoitum). However, heart beating was observed among
the majority of viable PRIP null embryos recovered between E11.5 and
E12.5 and few were moribund or dead. These observations indicate
lethality occurred in a relatively narrow window of time as no viable
PRIP null embryos were seen at E13.5. The viable PRIP
/
embryos recovered at E11.5 and E12.5 exhibited clear evidence of growth
retardation compared with the wild type and heterozygous littermates.
PRIP
/
embryos appeared strikingly different at the
gross level at E12.5, they were pale and smaller in size than their
PRIP+/+ and PRIP+/
littermates (Fig.
2, A and B).
Normally, extraembryonic mesoderm of the yolk sac gives rise to blood
and endothelial cells, which form blood islands. The extraembryonic
membrane covering PRIP null embryos contained fewer vessels in contrast
to wild type yolk sac with its well developed blood vessels (Fig.
2B). In addition, superficial vasculature was less obvious
in PRIP null mutants (Fig. 2D). While the liver of wild type
embryos was easily visualized by its rich vasculature through the skin,
only a pale primitive liver bud was discerned in PRIP
/
embryos (Fig. 2D). Failure of palatal shelf to fuse,
abnormal finder separations, and developmental abnormalities in brain
were detected in PRIP
/
mutants (not illustrated).

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Fig. 2.
PRIP /
mutants are developmentally retarded. Wild type
(A) embryo at E12.5 reveals yolk sac with well developed
blood islands, while the PRIP / littermate
(B) is smaller in size with fewer blood islands in its yolk
sac (ys). C, external appearance of eye,
blood-enriched liver, and distal part of hind limb with separated
fingers (white arrow) in wild type embryo. D,
PRIP / embryo shows dilated leaking small vessels (white
arrowhead) and few large blood vessels. Pigmented tissue is thinner in
the dorsal portion of the eye (ey). The liver
(li) mass is small and pale in the PRIP /
embryo. Finger separation does not occur in the distal part of hind
limb (white arrow). Each pair of photographs was taken at
the same magnification.
|
|
Lack of Organized Spongiotrophoblast Layer in PRIP Mutant
Placenta--
In wild type placenta at E12.5 contains three distinct
trophoblast cell structures: the innermost labyrinthine layer, the intermediate spongiotrophoblast layer, and the outermost trophoblast giant cell layer. The labyrinthine zone formed by the fusion of chorion
with allantois is composed of extensively branched fetal blood vessels
and maternal blood sinuses among strands of diploid trophoblast cells
that separate the maternal blood sinuses from fetal blood vessels. In
PRIP null placenta, no compact layer of spongiotrophoblast cells was
observed between labyrinth zone and trophoblast giant cell layer.
Instead, islands of spongiotrophoblast-like cells dissociated from
trophoblast giant cell layer and migrating into the labyrinth zone were
common occurrence in PRIP
/
placenta (Fig.
3B). In wild type placenta
blood sinuses are filled with maternal blood cells throughout the
labyrinthine layer (Fig. 3, A, C, and
F), whereas most of the tortuous vessels in the
PRIP
/
placenta were enlarged, ruptured, and generally
empty (Fig. 3, B, D, and
F). While the chorioallantoic fusion appeared to occur in
PRIP mutant placenta, chorionic trophoblast cells clustered in
labyrinth had multiple nuclei, and these clusters showed insufficient blood vessel branching. These changes are reminiscent of some of the
placental defects observed in PBP null mutants (22, 24). However,
changes in PRIP
/
placenta appeared less profound when
compared with PBP
/
placenta (24). Nucleated fetal
erythroblasts in PRIP
/
placenta had irregular shaped
nuclei with very little cytoplasm (Fig. 3F). Trophoblast
cell proliferation in PRIP null placenta as assessed by PCNA
immunostaining was significantly lower than that observed in
PRIP+/+ placenta (data not shown).

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Fig. 3.
Frontal sections of placenta from E12.5 wild
type (A, C, and E)
and PRIP /
mutant (B, D, and F)
embryos. A, H&E staining of wild type placenta
shows labyrinth region (La) with extensive well developed
fetal vessels surrounded by blood sinuses containing enucleated
maternal erythrocytes. The spongiotrophoblast layer (Sp) is
distinct in wild type placenta. B, in PRIP /
placenta, maternal blood sinuses are generally absent in most areas of
labyrinth zone. No organized spongiotrophoblast layer is present.
C and D, close-up view of labyrinth region shows
cells with multinucleus clusters in PRIP / placenta
(black arrowhead). Cellularization is less extensive
compared with the control. Nucleated fetal erythrocytes in the
PRIP / placenta (black arrow) exhibit
irregularly shaped nuclei and have scant cytoplasm compared with
control.
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|
PRIP
/
Embryos Manifest Cardiac
Defects--
Inefficient pumping by the heart leading to circulation
failure is one of the major causes of embryonic lethality during middle gestation. The development of heart requires coordinated
differentiation of several embryonic lineages, including the myocytes
of myocardium, the endothelial cells of the endocardium, and the cells
of the neural crest that form the outflow tract. At E12.5, the heart of
PRIP
/
embryos exhibited defects involving all three
lineages (Fig. 4, A and
B). In PRIP
/
heart, the epicardium,
consisting of a single layer of mesothelial cells lining against the
compact layer of myocardium, appeared to separate from underlying
myocardium and this space is filled with blood cells (Fig.
4B). Pericardial space surrounding the heart in mutant was
much smaller than their wild type littermate. Unlike the ventricles in
wild type heart, which consisted of multicell thick compact layer with
well developed trabeculae, the ventricles in PRIP
/
heart only contained one or two cell layers of myocardium (Fig. 4).
Cell-cell adhesion among cardiocytes appeared to be defective, which
possibly contributes to leakage of blood cells into epicardial spaces.
Cell proliferation in PRIP
/
myocardium was markedly
reduced as compared with PRIP+/+ myocardium (Fig. 4,
C and D). The failure of ventricular myocardium of PRIP
/
embryos to stratify into the multilayer
compact structure required to sustain adequate cardiac function appears
similar to that noted in PBP null and PPAR
null mutants (22, 24,
30).

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Fig. 4.
A and B, histological
analysis of sagittal sections of heart ventricle from E12.5 of wild
type (A) and PRIP / (B) embryos.
Trabeculation (t) is less extensive in PRIP /
embryo than in the wild type littermate. The compact layer
(cl) of the mutant is significantly thinner. Epicardium
(ep) in mutant is separated from underlying myocardium. In
some regions of compact layer of PRIP / , the adhesion of
myocytes was disrupted and red blood cells penetrated through
myocardium (arrowheads). C and D, PCNA
staining for the proliferating cells in ventricles of E12.5 wild type
(C) and PRIP / (D) embryos. Fewer
dark brown PCNA-positive cells are present in the compact
layer of PRIP / ventricle.
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Defective Hepatopoiesis and Hepatic Hematopoiesis in
PRIP
/
Mutants--
Liver of PRIP null mutants appeared
considerably smaller in size when compared with their littermates (Fig.
5, A and B). The function of the liver at E12.5 days is to become the major site of
hematopoiesis so as to gradually replace yolk sac based hematopoiesis. Histological examination of PRIP
/
liver revealed
reduction in hepatocyte population and an increase in hepatocyte
apoptosis (Fig. 5D). A marked decrease in the number of
erythroid progenitors was also evident, and these cells had large
nuclei with scant minimally hemoglobinized cytoplasm. Liver exhibited
large numbers of megakaryocytes.

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Fig. 5.
H&E staining of liver sections from wild type
and PRIP /
embryos. At low modification, liver (li) in
PRIP / embryo (B) is greatly reduced in size
than that of wild type liver (A). Liver of mutant contains
large numbers of megakaryocytes (white arrowhead), fewer of
erythrod progenitors (black arrowhead), and many cells with
apoptotic bodies (white arrowhead), in contrast to the
normal liver (C). The inset in D shows
a closer view of the apoptotic cells in liver PRIP /
liver.
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|
Differential Reduction of Transactivation by Nuclear Receptors in
PRIP
/
Primary Fibroblasts--
To assess the impact of
loss of PRIP on transcriptional activities of nuclear receptor, we
isolated MEFs from PRIP
/
and PRIP+/+
embryos. They were used for assaying the transcriptional activities of
PPAR
, RXR, and RAR. In wild type MEFs transfected with a RXR expressing vector and RXR-responsive element-linked reporter, the
addition of RXR-ligand 9-cis-retinoic acid induced marked increase (~76-fold) in the transcription (Fig.
6A). In PRIP
/
MEFs, the induction of ligand-mediated RXR transcription was markedly
reduced (~3-fold). Transcription assays with PPAR
(Fig. 6B) and RAR
(data not shown) showed that the influence of
PRIP was only modest. These results demonstrated that nuclear receptors require PRIP to achieve their full transcriptional potential, although
the contribution of PRIP to the activities of the three nuclear
receptors examined here differed somewhat in that PRIP seemed to
influence RXR maximally.

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Fig. 6.
Attenuated transcriptional activity of
nuclear receptors in
PRIP /
MEFs. MEFs isolated from E11.5 wild type, heterozygous, and
homozygous embryos were cotransfected with 1.5 µg of reporter
constructs, 20 ng of vectors expressing nuclear receptors, and
0.1 µg of pCMV in the presence or absence of the ligands. The
activities of the reporter obtained from transcfection with MEFs from
wild type embryos in the absence of ligand was taken as 1. The
transfections performed with RXR/RXRE (A), PPAR /PPRE
(B), and RAR/RARE (not illustrated). The results are the
mean ± S.D. of three independent transfections and are normalized
to the internal controls of -galactosidase expression.
|
|
 |
DISCUSSION |
The nuclear hormone receptors comprise a superfamily of
transcription factors that regulates coordinated expression of gene networks involved in developmental, physiological, and metabolic processes (1). Notable among this nuclear receptor superfamily is PPAR
subfamily comprising of three isoforms, PPAR
, PPAR
, and
PPAR
/
, since these receptors have emerged in recent years as a
critical player in regulating energy metabolism. In an effort to
understand the factors controlling cell and gene specific
transcriptional events initiated by nuclear receptors, the
ligand-binding domain of nuclear receptors was used in the yeast
two-hybrid screen to identify receptor interacting proteins (2-7, 31).
During the past 7 years, more than 25 nuclear receptor coactivators
have been cloned raising the issue of redundancy, since these
coactivators generally appear promiscuous in their coactivation potential.
To fully appreciate the in vivo biological functions of
these coactivators, molecular genetic approaches are being increasingly employed. Previous studies have demonstrated that mice lacking SRC-1 or
p/CIP/SRC-3 are viable and manifest either partial or full redundancy
for certain nuclear receptor actions (32-36). In contrast, deletion of
more general coactivators such as CBP/p300 and PBP in mice leads to
embryonic lethality implying that these are essential coactivators
(20-24). Thus, there appear to be at least two broad classes of
coactivators: essential and redundant. Our observations reported here
now add coactivator PRIP to the class of essential coactivators because
of the embryonic growth retardation, defects in placental, cardiac and
hepatic development, and embryonic lethality. Embryonic lethality was
noted between E11.5 and E12.5 days with no viable embryos at E13.5.
Defects were noted in heart (reduced amount of myocardium and
noncompaction), liver (small liver with reduction in hepatocyte
population, and hepatocyte apoptosis), and defects in erythropoiesis
(reduced hemoglobinization) and placenta (maturation block of
trophoblast with vascularization defect). The placental defects,
although not as pronounced as those encountered in PBP
/
placenta (22, 24), nevertheless compromise fetal-maternal exchange of
nutrients, growth factors, and oxygen, which may contribute to
embryonic growth retardation. The death of embryos at about mid-gestation has been reported in a number of null mutants induced by
gene targeting, including PPAR
(30), RXR
(37), PBP (22-24), and
N-myc (38).
It should be noted that we isolated both PRIP and PBP using PPAR
as
bait in the yeast two-hybrid screen and identified them as nuclear
receptor coactivators (9, 10). PBP has since emerged as a central piece
in large TRAP-DRIP-ARC-PRIC multiprotein cofactor complex
(17-19, 27). Recent studies have established that PBP is indispensable
for embryonic development because PBP null mutation leads to embryonic
death around E11.5 of mouse development (22-24). PBP null mutation
also causes defects in the development of placental vasculature similar
to those encountered in PPAR
mutants, supporting the requirement of
PBP for PPAR
function in vivo (22, 24, 30). PBP null
mutants also exhibited cardiac failure because of noncompaction of the
ventricular myocardium and resultant ventricular dilatation (22-24).
There was also paucity of retinal pigment, excessive systemic
angiogenesis, a deficiency in the number of megakaryocytes, and an
arrest in erythrocyte differentiation (24). We showed that PBP
interacts with GATA family of transcription factors and thus influences
the development of vital organ systems (24). Consistent with this view
is that the gene encoding PBP is amplified and overexpressed in breast
cancer (39). Like PBP, PRIP is also highly amplified/overexpressed in
human breast and colon tumors (11), suggesting that both PBP and PRIP
by virtue of their coactivating function may augment cell proliferation and neoplastic progression. Finally, the PRIP null MEFs exhibited marked repression of RXR-mediated transcriptional activity as compared
with PPAR and RAR. These observations strongly suggest that PRIP has
better preference for RXR than other nuclear receptors, and some of the
abnormalities noted in PRIP null mutants may be due to inhibition of
RXR function. Further studies are needed to examine the role of PRIP in
various tissues by generating PRIP conditional null mice.
Published, JBC Papers in Press, November 22, 2002, DOI 10.1074/jbc.C200634200
The abbreviations used are:
SRC-1, steroid receptor coactivator-1;
PPAR, peroxisome proliferator-activated
receptor;
PRIP, PPAR-interacting protein;
PBP, PPAR-binding protein;
PIMT, PRIP-interacting protein with methyltransferase activity;
RXR, retinoid X receptor;
PPRE, peroxisome proliferator response element(s);
RAR, retinoic acid receptor;
RARE, retinoic acid response element;
CREB, cAMP response element-binding protein;
CBP, CREB-binding protein;
TRAP, thyroid hormone receptor-associated protein(s);
DRIP, vitamin
D3 receptor-interacting proteins(s);
ARC, activator-recruited cofactor;
PRIC, PPAR
-interacting cofactor
complex;
ES cells, embryonic stem cells;
RT, reverse
transcriptase;
PCNA, proliferating cell nuclear antigen;
MEF, mouse
embryonic fibroblast.
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