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Metabolic Research Unit University of California, San Francisco, California 94143-0540
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(C/EBP) (6), Zn15 (7), estrogen
receptor (ER) (8, 9, 10), Ets-1 (11), c-jun (12), and pituitary
LIM homeodomain factor (P-LIM) (13). Some of these transcriptional
synergies are strongly dependent upon protein kinase activation (4, 5, 11) and, in those synergies involving TR or ER, hormone concentration
(4, 8, 9, 10). Thus, pituitary cell-specific transcription is mediated by
environment-sensitive synergies between transcription factors, most of
which are present in a wide variety of nonpituitary cells in which they
do not influence GH or PRL transcription. Most other promoters are also activated cell specifically by factors of a comparatively broad tissue distribution. Although isolated transcription factor activities seem to be secondary to synergistic activities in the formation of expression patterns that determine cell identity, the mechanisms by which the synergistic partners affect each other’s activities remain largely unknown. Of the few studies of transcriptional synergy, the synergistic activations of the rGH promoter by Pit-1 and TR and of the rPRL promoter by Pit-1 and ER are possibly the best characterized. Because the rGH and rPRL genes (14), as well as TR and ER (15, 16, 17), are evolutionarily related and because GH and PRL are expressed in developmentally related anterior pituitary cell types (8, 18, 19, 20, 21), comparing Pit-1/TR synergy at the rGH promoter (4, 5) with Pit-1/ER synergy at the rPRL promoter (8, 9, 10) will allow us to delimit common and unique mechanisms involved in transcriptional synergy. Previous studies of Pit-1/TR synergy at the rGH promoter (5) and Pit-1/ER synergy at the rPRL promoter (10) suggested that both synergies depend upon overlapping but clearly unique activities in Pit-1,but this conclusion is limited by the differences in the experimental and cellular systems used in these separate studies. Nothing is yet known of the effects of any of the recently identified nuclear receptor coactivators on these, or any other, synergies.
Here, we demonstrate that identical activities in Pit-1 are required
for Pit-1/TR and Pit-1/ER synergy under identical experimental
conditions. Both synergies also depended upon activation function-2
(AF-2), conserved in TR and ER. Expression of an AF-2 interacting
protein RIP140 (22) selectively inhibited both Pit-1/TR synergy at the
rGH promoter and Pit-1/ER synergy at the rPRL promoter. Inhibition by
RIP140 was profoundly affected by activities within Pit-1 in a
promoter-specific fashion. Deletion of Pit-1 of amino acids (aa)
101–125 eliminated RIP140 inhibition of Pit-1/ER synergy at the rPRL
promoter but had no effect on RIP140 inhibition of Pit-1/TR synergy at
the rGH promoter. Intriguingly, RIP140 expression caused the otherwise
synergy-deficient 
72–100 deletion of Pit-1 to synergize with ER at
the rPRL promoter. Deleting Pit-1 aa 72–100 similarly activated a
latent, RIP140-dependent, Pit-1/TR synergy at the rPRL promoter but not
at the rGH promoter. Thus, activities within Pit-1 dictate whether a
factor binding to a nuclear receptor inhibits, has no effect on, or
activates synergy. This interplay of transcription factors and
coactivators is influenced by promoter-specific elements or factors and
is likely crucial to the determination and maintenance of cell-specific
expression patterns.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). Pit-1 and ER
Western blots conducted on extracts subsequently prepared from the
nuclear pellet proved this activation to be genuinely synergistic and
not simply due to enhanced expression of either Pit-1 or ER (Fig. 1, B
and C). For these Westerns, Pit-1 was tagged at its amino terminus with
the FLAG epitope to distinguish transiently expressed Pit-1 (Fig. 1B)
from endogenous Pit-1. An antibody that preferentially, although not
exclusively, recognized hER was used to distinguish transiently
expressed hER (Fig. 1C) from the endogenous mouse ER that we observed
to be present in GHFT1–5 cells.
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) also was mostly estradiol-dependent (data not
shown) demonstrating that Pit-1 synergizes with endogenous ER present
in GHFT1–5 cells as well as with coexpressed ER. Pit-1/ER synergy was
observed in the absence of the protein kinase A and protein kinase C
activators, forskolin and phorbol 12-myristate 13-acetate (PMA), which
activated synergy only 1.6-fold on average (data not shown). This
contrasts with Pit-1/TR synergy at the rGH promoter, which was wholly
dependent upon incubating transfected GHFT1–5 cells with forskolin and
PMA (5). To permit further direct comparisons between Pit-1/ER synergy
at the rPRL promoter with Pit-1/TR synergy at the rGH promoter under
the same conditions, all subsequent experiments were performed in
GHFT1–5 cells incubated with forskolin and PMA. Thus, Pit-1 and ER
synergistically activate the rPRL promoter in an excellent pituitary
cell culture model, confirming that Pit-1/ER synergy observed in some
nonpituitary cell types (8, 9, 10) is likely relevant to pituitary
biology.
Pit-1 Activities Required for Pit-1/ER Synergy at the rPRL
Promoter
The same set of Pit-1 mutations used to determine the activities
in Pit-1 necessary for Pit-1/TR synergy at the rGH promoter in GHFT1–5
cells (5) was used to determine that grossly similar activities in
Pit-1 were required for Pit-1/ER synergy at the rPRL promoter (Fig. 2). Pit-1 deletions within a previously described (5, 24) activation function residing within aa 2–73 supported neither
activation by Pit-1 alone nor synergy with ER (Fig. 2A). Therefore,
Pit-1/ER synergy, like Pit-1/TR (5) synergy, required active
participation by Pit-1.
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72–125 mutant of Pit-1 were
equally capable of activating a minimal promoter to which only
Pit-1-binding sites were appended (5). At the rPRL promoter, we
observed a 2.2-fold activation, on average, by Pit-172–125 in the
absence of coexpressed ER that was similar to the 2.8-fold activation
by wild type Pit-1 alone in the absence of estradiol (data not shown).
By contrast, in the presence of estradiol and in synergy with
endogenous ER (Fig. 2B), the 2.2-fold activation by Pit-172–125 was
significantly less than the 4.8-fold enhancement by wild type Pit-1
(Fig. 2B). This suggested that Pit-1/ER synergy at the rPRL promoter in
GHFT1–5 cells was much more sensitive to the deletion of Pit-1 aa
72–125 than was activation by Pit-1 alone, which was confirmed by the
finding that Pit-172–125 did not act in synergy with coexpressed
hER (Fig. 2B). We refer to this region as SynAF-1 to reflect its
selective participation in synergy with both ER (Fig. 2B) and TR
(5).
As with Pit-1/TR synergy at the rGH promoter (5), the SynAF-1
requirement for Pit-1/ER synergy at the rPRL promoter mapped to Pit-1
aa 72–100 (Fig. 2B). Pit-1, with aa 101–125 alone removed, behaved as
wild-type Pit-1 in the Pit-1/ER synergistic activation of the rPRL
promoter whereas Pit-1, with aa 72–100 removed, like Pit-172–125,
did not synergize with ER. Western blots of FLAG-tagged 72–100 and
101–125 Pit-1 mutants showed that both were efficiently expressed
in GHFT1–5 cells (Fig. 3; activation of rPRL promoter
activity by expression of each Pit-1 alone is presented for the
experiment from which the representative Western blot was taken). The
efficient expression of these Pit-1 mutants agrees with our previous
findings that the Pit-172–100 and Pit-1101–125 mutants
activated a minimal, Pit-1-sensitive promoter as effectively as wild
type Pit-1 under identical assay conditions (5). Thus, a series of
activities in Pit-1 including activation functions residing between aa
2 and 73 and a synergism-selective activity dependent upon aa 72–100
are required for both Pit-1/ER and Pit-1/TR synergies at the rPRL and
rGH promoters.
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). Thus, in addition to similarly
requiring independent and synergism-selective activation functions
within Pit-1, both Pit-1/TR and Pit-1/ER synergistic activation require
the conserved nuclear receptor AF-2.
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). RIP140 also reduced expression
from the rPRL promoter activated by Pit-1 "alone" probably by
affecting Pit-1 synergy with low levels of endogenous ER. A trivial
explanation for RIP140 inhibition of synergy might be that RIP140
inhibited ER and/or Pit-1 synthesis from their expression vectors.
Western blots indicated that RIP140 had no effect on the expression of
hER (detected with the hER antibody, Fig. 6B),
FLAG-Pit-1, or endogenous Pit-1 (both detected with a Pit-1 antibody
and distinguished by the larger size of FLAG-Pit-1, Fig. 6C), or
endogenous ER (Fig. 6D, detected with a rodent-specific ER antibody).
Thus, RIP140 directly abolished Pit-1/ER synergistic activation of the
rPRL promoter.
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(Fig. 5B) demonstrating that RIP140 inhibition was
selective for Pit-1/ER synergy. Other nuclear receptor-interacting
proteins including TIF1 (26), SRC-1 (29), GRIP1 (31), and CBP (32) did
not inhibit Pit-1/ER synergy although CBP enhanced C/EBP activation
of both the rGH and rPRL promoters in parallel experiments (our
unpublished data). RIP140 inhibition of synergy was retained when both
RIP140 and CBP were coexpressed (data not shown). RIP140 expression
similarly inhibited TR synergy with wild type Pit-1 at the rGH promoter
in GHFT1–5 cells (Fig. 7A) without affecting C/EBP
activation of the rGH promoter (our unpublished data). Thus,
Pit-1/nuclear receptor synergistic activation is acutely sensitive to
RIP140, which presumably interferes with AF-2 function. These results
strongly suggest that we should rethink the assumption that any factor
that binds to AF-2 in a ligand-dependent fashion always functions as a
coactivator.
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101–125 Mutation) and TR (5), but not with C/EBP (6),
and 2) RIP140, which selectively inhibited Pit-1/ER (Figs. 5, 6) and
Pit-1/TR (Fig. 7A) synergy without affecting C/EBP activation of the
rGH or rPRL promoters. To determine whether these two
synergism-selective effects were related, we studied the effects of the
72–100 and 101–125 Pit-1 mutants on RIP140 inhibition of
Pit-1/TR and Pit-1/ER synergy at the rGH and rPRL promoters (Fig. 7).
For simplicity, only shown are the effects of RIP140 expression on rGH
and rPRL promoter activity when Pit-1 or mutants thereof are
coexpressed with the indicated nuclear receptor.
Pit-1 with aa 101–125 deleted still synergized with ectopically
expressed ER (Fig. 2B) and TR (5). However, ER synergy with
Pit-1101–125 at the rPRL promoter was no longer or, at best poorly,
inhibited by RIP140 expression (Fig. 7D). This contrasts with
Pit-1101–125/TR synergy at the rGH promoter, which was still
inhibited by RIP140 expression (Fig. 7C). Similarly, RIP140 inhibition
of Pit-1 synergy with endogenous ER was eliminated by deleting Pit-1 aa
101–125: in synergy with endogenous ER, Pit-1101–125 activation of
the rPRL promoter was not inhibited by RIP140 expression (89.0 ±
20.3% as active as the Pit-1101–125-activated promoter in the
absence of RIP140) whereas wild type Pit-1 was inhibited to 58.6
± 4.8% the activity in parallel experiments (n = 5). Thus, an
activity dependent upon Pit-1 aa 101–125 is required for the RIP140
inhibition of Pit-1/ER synergy at the rPRL promoter. This demonstrates
that activities within one transcription factor influence the
transcriptional effect of a coactivator interacting with its
synergistic partner. This influence is somehow altered by other
elements specific to the rGH or rPRL promoters or to the TR and ER
themselves.
A SynAF-1 Mutant of Pit-1 that Switches RIP140 from an Inhibitor to
an Activator of Pit-1/ER Synergy
Surprisingly, coexpression of the synergy-defective
Pit-172–100 mutant with ER resulted in RIP140-dependent activation,
not inhibition, of the rPRL promoter (Fig. 7F). Again, this effect was
rPRL-specific as the Pit-172–100 mutant did not synergize with TR
at the rGH promoter (Fig. 7E). This activation represented bona
fide RIP140-dependent synergy because it was observed only when
all three factors (Pit-172–100, ER, and RIP140) were coexpressed
(Fig. 8A). Thus, when deleted of aa 72–100, Pit-1 is
defective in synergy with ER unless RIP140 is added. This activation of
Pit-172–100 synergy by RIP140 contrasts starkly with the inhibition
of wild type Pit-1/ER synergy by RIP140. In contrast, the similarly
synergy-defective Pit-172–125 mutant did not synergize with RIP140
and ER (data not shown), demonstrating that Pit-1 aa 101–125 were
required for the RIP140-dependent Pit-172–100/ER synergy. Like
RIP140 inhibition of wild type Pit-1/ER synergy, RIP140 activation of
Pit-172–100/ER synergy therefore requires Pit-1 aa 101–125.
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).
RIP140 expression did not change the absence of TR synergy with wild
type Pit-1 or Pit-1101–125 (data not shown). In contrast, deletion
of Pit-1 aa 72–100 resulted in a RIP140-dependent, Pit-1/TR synergy at
the rPRL promoter (Fig. 8B). Therefore, as with Pit-1/ER synergy at the
same rPRL promoter (Fig. 8A), the deletion of Pit-1 aa 72–100
activated a latent synergy with TR and with a coactivator that
interacts directly with TR. This result suggests that the differences
in SynAF-1 effects on RIP140 modulation of Pit-1/nuclear receptor
synergies are related to promoter-specific activities other than simple
differences in TR and ER. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Very little is known of the molecular events of such transcriptional
synergies despite their undoubted importance to gene expression. We
compared activation of the phyllogenetically and ontologically related
rGH and rPRL genes to define activities required for Pit-1/nuclear
receptor synergies. Both synergies required activation functions (Fig. 9, AF) in both Pit-1 and in the nuclear receptors (Ref.
5 , Figs. 2A and 4) indicating that both partners actively participated
in activation. Both synergies were inhibited by the expression of
RIP140 (
Figs. 5–7), which likely occurred by RIP140 interference with
AF-2, possibly by competing for AF-2 binding with a hypothetical
strong, endogenous coactivator (Fig. 9). An equally viable alternative
not depicted in Fig. 9 is that RIP140 actively inhibited synergy. We
currently prefer the scheme outlined in Fig. 9 only because it is the
simplest explanation for all of our data regarding the ability of
RIP140 to both activate and repress synergy.
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). The latter
results differed somewhat from those reported for Pit-1/ER synergistic
activation of the rPRL promoter in CV-1 cells (10) in which
synergism-selective effects were observed by the deletion of aa 45–72
(compare with our Pit-148–73 which disrupts both activation by
Pit-1 alone and synergy with nuclear receptors, Fig. 2A) and in which
the analogous deletion of Pit-1 aa 73–128 Pit-1 did not prevent
Pit-1/ER synergy. These cell-specific observations are likely related
to cell-specific differences in the distribution of other transcription
factors and highlight the necessity of comparing Pit-1/TR and Pit-1/ER
synergies at the rGH and rPRL promoters under identical experimental
conditions.
Although Pit-1/nuclear receptor synergies at the rGH and rPRL promoters
were grossly similar, the synergy was influenced in a promoter-specific
fashion by other factors or events. Mutations within SynAF-1 determined
whether RIP140 inhibited or activated Pit-1 synergy with ER or TR
specifically at the rPRL promoter (Figs. 7 and 8). The regulatory
properties of this SynAF-1/AF-2 synergy switch were subtly different
between synergy itself and RIP140 modulation thereof: Pit-1 aa 101–125
were not required for raw synergy but were required for RIP140
regulation (both activation and inhibition) at the rPRL promoter (Fig. 9); Pit-1 aa 72–100 were required for raw synergy and therefore either
prevented synergy in the presence of RIP140 (Fig. 9) or actively
supported inhibition by RIP140 (not depicted). The differential rGH
(Fig. 7E) and rPRL (Fig. 8B) promoter response under identical
experimental conditions suggested that elements or factors specific to
the rGH or rPRL promoters could modulate the SynAF-1/AF-2 synergy
switch and dramatically alter gene transcription. Candidates for the
promoter-specific activity include promoter-specific binding factors,
differences in Pit-1/nuclear receptor binding site orientation and
spacing, or the known difference in dimeric status of Pit-1 or TR bound
to certain sites (10, 17).
Thus, a molecular ménage-à-trois involving Pit-1, nuclear receptors, RIP140, and probably other AF-2-interacting proteins governs synergistic transcriptional activation of the rGH and rPRL promoters in GHFT1–5 pituitary progenitor cells and is differentially influenced by promoter structure. It will be very important to characterize this synergy switch involving SynAF-1, its interdependence with AF-2-binding coactivators and with transcriptional activation functions in both Pit-1 and nuclear receptors, and to determine how components of this switch are altered in different physiological and developmental expression states (8, 20, 36, 37, 38, 39, 40). The finding that coactivator action can be influenced by specific combinations of transcription factor activities can be explained by numerous models, but it would appear that the activities that participate in Pit-1/nuclear receptor synergy, possibly including an endogenous GHFT1–5 cell AF-2-interacting protein, are skewed or usurped by the AF-2-interacting protein, RIP140. The complexity and interrelatedness of these activities demonstrate the necessity of ultimately viewing transcriptional events at complete, natural promoters to understand gene expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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For Westerns, the cell pellet posttreatment with reporter lysis buffer
was resuspended in 2-(N-morpholino)ethanesulfonic acid-Tris
(pH 7.8), 1 mM dithiothreitol, and 0.1% Triton X-100,
pelleted, resuspended in the same buffer, and pelleted again. The
resulting crude nuclei were resuspended three times with 20 µl of 20
mM HEPES (pH 7.9), 300 mM KCl, 200
mM NaCl, 1 mM EDTA, 0.1% NP-40, and 15%
glycerol and the extracts were pooled. Equivalent amounts of extract
protein (5–20 µg depending on the experiment) were loaded onto SDS
acrylamide gels and probed with either the FLAG M2 antibody
(ICI-Kodak, Rochester, NY), the Pit-1 214–230 antibody (Berkeley
Antibody Company, Berkeley, CA), the human-specific ER HC-20 antibody
(Santa Cruz Biotechnology, Santa Cruz, CA) or the rodent-specific ER
MC-20 antibody (Santa Cruz Biotechnology). Rat PRL promoter activity
normalized to cytoplasmic extract protein is shown in Figs. 1, 3 and 6
for direct comparison with Pit-1/ER expression level determined by
Western blots on nuclear extracts.
Plasmids
Two and five-tenths micrograms of the -237/+8 rGH
promoter (where +1 is the transcription start site) cloned in front of
the chloramphenicol acetyltransferase gene (4) or 2.5 µg of the -3
kb rPRL promoter/enhancer cloned in front of the luciferase gene (41)
were transfected in each experiment shown. Each promoter was
cotransfected with 10 µg of the indicated TR or ER expression vectors
or cognate expression vectors not containing an inserted cDNA. The hTR
(6) or hER (42, 43) expression vectors have been previously described.
FLAG-tagged Pit-1 was constructed by inserting an oligonucleotide
encoding the amino acids MDYKDDDDKDYA with an optimal Kozak sequence
into an NcoI site overlapping the initiator Met of Pit-1.
Five micrograms of FLAG-tagged Pit-1, cloned behind the cytomegalovirus
(CMV) promoter in the vector Rc/CMV (Invitrogen, San Diego, CA), were
transfected (Figs. 1, 3, and 6) whereas 10 µg of the unmodified Pit-1
expressed from the previously described (4) Rous sarcoma virus promoter
were transfected in the remaining experiments. Equivalent amounts of
cognate expression vectors not containing an inserted cDNA were
substituted for transfections in which Pit-1 was not expressed. In
experiments in which the amounts of FLAG-tagged wild type and mutant
Pit-1 were varied (Fig. 3 and data not shown), the decreased amount of
FLAG-tagged vector was supplemented with Rc/CMV to 5 µg.
The Pit-1 mutants were identical to those used previously (5, 24). The
point mutation in AF-2 of TR was constructed by
oligonucleotide-directed mutagenesis in which the glutamic acid at aa
451, conserved in most AF-2 sequences, was changed to lysine. The
L543A/L544A AF-2 double-point mutation in AF-2 of mouse ER was
previously described (44), and the cognate mouse wild type ER
expression vector was used as the control in Fig. 4A. The RIP140
expression vector was previously described (2), and maximal inhibition
of synergy was observed with the 10 µg of expression vector used in
all of the experiments presented here.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by Grant BE-195 from the American Cancer Society (to F.S.)
Received for publication February 13, 1997. Revision received May 14, 1997. Accepted for publication May 16, 1997.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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activation of the rat growth
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F. F. Wiebel, K. R. Steffensen, E. Treuter, D. Feltkamp, and J.-A. Gustafsson Ligand-Independent Coregulator Recruitment by the Triply Activatable OR1/Retinoid X Receptor-{alpha} Nuclear Receptor Heterodimer Mol. Endocrinol., July 1, 1999; 13(7): 1105 - 1118. [Abstract] [Full Text]
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N. Subramaniam, E. Treuter, and S. Okret Receptor Interacting Protein RIP140 Inhibits Both Positive and Negative Gene Regulation by Glucocorticoids J. Biol. Chem., June 18, 1999; 274(25): 18121 - 18127. [Abstract] [Full Text] [PDF]
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G. N. Lopez, P. Webb, J. H. Shinsako, J. D. Baxter, G. L. Greene, and P. J. Kushner Titration by Estrogen Receptor Activation Function-2 of Targets That Are Downstream from Coactivators Mol. Endocrinol., June 1, 1999; 13(6): 897 - 909. [Abstract] [Full Text]
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F. Schaufele Regulation of Estrogen Receptor Activation of the Prolactin Enhancer/Promoter by Antagonistic Activation Function-2-Interacting Proteins Mol. Endocrinol., June 1, 1999; 13(6): 935 - 945. [Abstract] [Full Text]
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 C.-H. Lee, C. Chinpaisal, and L.-N. Wei Cloning and Characterization of Mouse RIP140, a Corepressor for Nuclear Orphan Receptor TR2 Mol. Cell. Biol., November 1, 1998; 18(11): 6745 - 6755. [Abstract] [Full Text] [PDF]
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R. N. Day Visualization of Pit-1 Transcription Factor Interactions in the Living Cell Nucleus by Fluorescence Resonance Energy Transfer Microscopy Mol. Endocrinol., September 1, 1998; 12(9): 1410 - 1419. [Abstract] [Full Text]
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E. Treuter, T. Albrektsen, L. Johansson, J. Leers, and J.-A. Gustafsson A Regulatory Role for RIP140 in Nuclear Receptor Activation Mol. Endocrinol., June 1, 1998; 12(6): 864 - 881. [Abstract] [Full Text]
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L.-N. Wei, X. Hu, D. Chandra, E. Seto, and M. Farooqui Receptor-interacting Protein 140 Directly Recruits Histone Deacetylases for Gene Silencing J. Biol. Chem., December 22, 2000; 275(52): 40782 - 40787. [Abstract] [Full Text] [PDF]
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L.-N. Wei, M. Farooqui, and X. Hu Ligand-dependent Formation of Retinoid Receptors, Receptor-interacting Protein 140 (RIP140), and Histone Deacetylase Complex Is Mediated by a Novel Receptor-interacting Motif of RIP140 J. Biol. Chem., May 4, 2001; 276(19): 16107 - 16112. [Abstract] [Full Text] [PDF]
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