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Department of Medicine (S.L., D.E.E.) Baylor College of
Medicine Houston, Texas 77030
Department of Urology
(G.J.) Erasmus University Rotterdam, The Netherlands
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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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Recent studies indicate that androgen regulates several cell cycle-regulatory molecules within prostate epithelial cells. For instance, androgen increases expression and enzymatic activities of cyclin-dependent kinases (CDK) 2 and 4, molecules that generally promote cell proliferation (11). Androgen has variable effects on CDK inhibitors: it inhibits expression of p16 (MTS1, CDKN2), a member of the p16 family of CDK inhibitors (11), whereas it increases expression of p21 (WAF1, CIP1, SDI1, CAP20), which belongs to a second family of CDK inhibitors (12). p21 was first identified as a CDK inhibitor and later was found to be involved in various biological processes, such as cell cycle control, DNA repair, and antiapoptosis (13, 14, 15). p21 induces cell cycle arrest in response to DNA damage and protects cancer cells against p53-mediated apoptosis. These studies revealed a novel class of genes involved in an androgen-signaling pathway.
Regulation of p21 expression has been studied extensively. p21 gene is induced by p53 (16), transforming growth factor-ß (TGF-ß) (17), signal transducer and activator of transcription 1 (STAT1) (18), vitamin D (19), and nerve growth factor (NGF) (20). The corresponding cis-regulatory elements for each of these factors have been identified in the p21 promoter. We recently found that p21 expression is also activated by androgen via a canonical ARE in its proximal promoter region (12). Androgen up-regulates expression of the p21 gene in stimulating prostate cancer cell proliferation, indicating that the major function of p21 in the prostatic epithelial cells is not cell cycle block. In situ hybridization studies showed that all prostatic epithelial cells, but only a few stroma cells, express p21 protein (21). The functional significance of p21 expression in the prostatic epithelial cells in an androgen-regulated manner is not clear.
The present studies were carried out to further investigate the molecular mechanisms of androgen induction of the p21 gene. We found that, in addition to a canonical ARE in the core promoter of the p21 gene, Sp1 binding sites are also involved in the induction of p21 by androgen. We also present evidence that transcription factor Sp1 and androgen receptor (AR) interact with one another. These findings suggest a novel molecular mechanism by which androgen regulates expression of its target genes.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the current study, we determined whether cis-regulatory
elements in the p21 core promoter in addition to the ARE mediate
androgen action. To do so, we used transient transfection assays with
various p21 promoter-luciferase reporter constructs. We found that
construct p21(-215)-Luc containing 215 bp of the p21 promoter,
including the ARE, conferred 6.2-fold induction by androgen in
AR-positive LNCaP-FGC cells (Fig. 1
).
Elimination of the ARE did not completely eliminate androgen
responsiveness. Construct p21(-190)-Luc, which contained 190 bp of
the p21 promoter but lacked the ARE, retained 2.8-fold induction by
androgen. We therefore hypothesized that the p21 promoter contains
cis-regulatory elements in addition to the ARE that mediate
androgen responsiveness.
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). We next investigated whether the Sp1 sites play a role in
androgen induction of the p21 gene. To do so, we used a series of
reporter constructs containing the p21 promoter sequence spanning -93
to +1 bp, in which 10-bp nucleotide blocks were progressively mutated
(Fig. 2). We found that construct
p21P93-s conferred approximately 4-fold induction by androgen,
indicating that the cis-elements involved in androgen
responsiveness are included in -93 
+1 bp sequence and that
Sp1–1 and Sp1–2 sites are not critical for this effect. Construct
p21P93-s mut2, in which the Sp1–3 binding site was destroyed, showed a
dramatic decrease of basal promoter activity and minimal androgen
responsiveness. In contrast, disruption of Sp1–4, Sp1–5, and Sp1–6
sites had relatively little effect on androgen responsiveness or basal
activity (Fig. 2), suggesting that the Sp1–3 site is the major
cis-element other than the ARE contributing to the basal
promoter activity and androgen responsiveness of the p21 gene. Mutation
of the TATA box did not eliminate the basal promoter activity and
androgen responsiveness of the p21 promoter, suggesting that the TATA
box is not critical for the promoter activity.
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) (22). As shown in Fig. 1D, both reporter
constructs pXP2-TG-Luc and pXP2-
CAAT-Luc, each containing four Sp1
sites with or without a CAAT box, did not respond to androgen
stimulation. For an additional control, minimal TK promoter construct
(bRE2-TK-Luc) linked with two tandem repeats of retinoid acid response
element (RARE) also did not respond to androgen treatment. These data
suggested that enhanced GC-rich core promoter activity conferred by
androgen stimulation is specific for the p21 promoter.
Interaction between Transcription Factor Sp1 and AR in Androgen
Induction of the p21 Gene Determined by Mammalian One-Hybrid Assay
Since both ARE and Sp1 binding sites in the p21 proximal promoter
were found to be involved in induction of the gene by androgen, we then
used the mammalian one-hybrid assay to investigate whether this effect
is mediated by interaction between AR and transcription factor Sp1 in a
ligand-dependent manner. The mammalian one-hybrid system has two
components: 1) a transcription factor that binds DNA and functions as
bait, and 2) a coactivator that interacts with the bait and also serves
a bridging function. The bridging function of the coactivator results
in recruitment of other coactivators and general transcription factors
to form a preinitiation complex, resulting in transcription of the
reporter gene. In our system, transcription factor Sp1 functioned as
bait and bound DNA at the Sp1 site(s). Coactivators consisted of fusion
proteins between full-length AR or the ligand binding domain
(ARLBD) of AR with the transactivation domain
from either viral protein 16 (VP16) or p65/RelA (p65) (Fig. 3A) (23). This system resulted in
androgen-dependent transactivation by these fusion proteins.
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, fusion proteins pcDNA-ARo-VP16 and pcDNA-ARo-p65
containing full-length AR sequence conferred 22.2-fold and 17.0-fold
induction of the p21 promoter activity by androgen, respectively. In
contrast, the control vectors pcDNA-VP16, pcDNA-p65, and
pcDNA-ARLBD containing either VP16 domain, p65
domain, or ARLBD domain, respectively, as well as
CMV empty vector, showed only 5- to 7-fold induction by androgen. This
relatively low level induction was probably due to endogenous
transcription factor Sp1 and AR interaction. These results demonstrated
that the fusion proteins containing full length AR enhanced p21
promoter activity in a ligand-dependent manner, suggesting that
transcription factor Sp1 and AR proteins complex with one another.
We then investigated whether the ligand-binding domain of AR alone can
interact with transcription factor Sp1. The mammalian one-hybrid assay
showed that fusion proteins pcDNA-ARLBD-VP16 and
pcDNA-ARLBD-p65 containing only the
ligand-binding domain conferred 12.6- and 98.3-fold induction by
androgen, respectively (Fig. 3B). These data indicated that AR binds to
transcription factor Sp1 via the ligand-binding domain of AR. However,
domains other than the ligand-binding domain of AR may also be involved
in binding transcription factor Sp1.
We next measured the affinity of two of the fusion proteins for AR
agonist R1881. R1881 at a concentration of 10-10
M dramatically increased the reporter activity driven by
pcDNA-ARo-VP16 containing full length of AR cDNA (Fig. 4A). The EC50 of
this fusion protein was approximately 5 x10-10
M of R1881, which is similar to that of endogenous AR in
LNCaP-FGC cells as measured by transactivation of the p21 promoter in a
transient transfection assay (12). In contrast, the fusion protein
pcDNA-ARLBD-p65, consisting of the AR
ligand-binding domain fused to the transactivation domain of p65, had a
low affinity for androgen with a EC50 of
10-9 M (Fig. 4B). Despite its low
affinity for androgen relative to pcDNA-ARo-VP16,
pcDNA-ARLBD-p65 had a greater transactivation
activity in the mammalian one-hybrid assays (Fig. 3B).
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) was used for these experiments, since it was found to have
the greatest transactivation function for wild-type p21 promoter as
compared with other fusion proteins (Fig. 3). The reporter construct
p21P93-s mut2, which contains a mutation within Sp1–3 site, showed a
low basal promoter activity and a minimal response to ligand
stimulation (Fig. 5). In contrast, the wild-type construct p21P93-s, as
well as constructs containing mutations within other Sp1 sites,
maintained high level induction by androgen (Fig. 5). These results confirmed the critical
role of the Sp1–3 site in maintaining basal activity and androgen
inducibility of the p21 promoter, as suggested by previous experiments
(Fig. 2).
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). AR also coimmunoprecipitated with
transcription factor Sp1 using anti-Sp1 antibody for
immunoprecipitation, as indicated by a detected band corresponding to
AR protein in response to androgen stimulation (Fig. 6A, lane2).
Reciprocally, transcription factor Sp1 was coimmunoprecipitated with AR
using anti-AR antibody for immunoprecipitation, indicated by an
enhanced precipitated Sp1 protein upon androgen stimulation (Fig. 6B).
Nuclear alteration of transcription factor Sp1 was not observed by
androgen stimulation. These data convincingly demonstrated the
interaction of AR and transcription factor Sp1.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Using the mammalian one-hybrid system, we also found that AR and
transcription factor Sp1 interact with one another. Based on these
results, we hypothesize that AR and transcription factor Sp1 form a
complex with one another upon binding to their respective sites within
the p21 promoter. Formation of this complex in response to androgen
could facilitate binding of other coactivators and general
transcription factors to form a preinitiation complex for gene
transcription (Fig. 7). The consequence
of this effect would be to enhance expression of the androgen target
gene p21.
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1 (30), vitellogenin A1 (31), and rabbit
uteroglobin (32) genes, despite the fact that none of the corresponding
promoters contain consensus estrogen response elements. Progesterone
similarly induces expression of the p21 gene, which does not contain a
consensus progesterone response element within its promoter (26). In
the current studies, we found that deletion of the ARE in the p21
promoter did not completely eliminate androgen responsiveness, whereas
mutation of the Sp1–3 site did. Our studies and previous ones
therefore suggest that steroid hormone receptors, such as ER, PR, and
AR, are capable of activating transcription of target genes by forming
a complex with transcription factor Sp1 and binding Sp1 sites in a
ligand-dependent manner rather than by binding classical hormone
response elements.
Cross-talk between pathway-specific transcription factors has been
demonstrated in various systems (33, 34). Nuclear hormone receptors are
engaged in cross-talk with many other transcription factors, such as
AP1, nuclear factor-
B/Rel, Stat, and C/EBP. Recently, with
cloning and characterization of transcription coactivators and
corepressors, the molecular mechanisms of transcriptional cross-talk
between transcription factors became even more complicated. A few
factors are needed to be considered for synergism or negative
interference of transcriptional cross-talk, including direct
interaction between transcription factors, indirect interaction through
"bridging protein," and competition for limiting amounts of
cofactors, promoter context, and genetic background of cells. For
example, interaction of GR and transcription factor AP1 is involved in
regulation of the mouse proliferin gene through a "composite
glucocorticoid response element" in a cell type-specific fashion
(35). When AP1 is composed of c-Fos and c-Jun heterodimer, negative
interference by GR will be observed; and when AP1 is a homodimer of
c-Jun, synergism is detected. Protein-protein interaction plays a major
role in transcriptional cross-talk (33, 34). Mutational analysis has
mapped the domains involved in cross-talk to the DNA-binding domain of
the nuclear receptor and the bZip domain of AP1. Positive regulations
between transcription factors are demonstrated in genes, such as
ovalbumin gene by ER, and Fos-Jun complex (36) and rat tryptophan gene
by GR and CACCC-box binding factors (37). Our present study showed a
positive interaction between AR and transcription factor Sp1 on
regulation of the p21 gene. The detailed molecular mechanisms of this
regulation remain to be determined.
Androgen impacts almost every organ in the body and can induce expression of many genes (5, 6). However, AREs were identified in only a few gene promoters. It is possible that androgen induces some of its target genes only via the Sp1 site when ARE is absent in these target gene promoters. This possibility will need to be confirmed with future studies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Reagents
R1881 was purchased from DuPont Merck Pharmaceutical Co. (Wilmington, DE).
Plasmids
p21-(-215)-Luc luciferase reporter vector includes a core
promoter sequence of the p21 gene spanning from -215 to +1 bp (12).
Construct p21(-190)-Luc was generated by inserting a PCR fragment
spanning -190 to +1 bp of the p21 promoter to a luciferase reporter
vector. Construct p21P93-S containing 93 bp p21 core promoter sequence
and its mutants p21P93-s mut1, p21P93-s mut2, p21P93-s mut3, p21P93-s
mut4, p21P93-s mut5, and p21P93-s mut6 were gifts from Dr. Xiao-Fan
Wang (Department of Pharmacology, Duke University Medical Center,
Durham, NC). Constructs pcDNA-ARo-VP16, pcDNA-ARo-p65,
pcDNA-ARLBD-VP16, pcDNA-ARLBD-p65, pcDNA-VP16, pcDNA-p65, and
pcDNA-ARLBD have been described previously (23).
Transient Transfection Assay
LNCaP-FGC cells (105) were seeded in
12-well tissue culture plates. Next day, lipofectin-mediated
transfection was used for the transient transfection assay according to
the protocol provided by Life Technologies, Inc. Cell
extracts were prepared according to in vitro luciferase
assay kit (Promega Corp., Madison, WI). Luciferase assays
were performed in a Monolight 2010 Luminometer (Analytical Luminescence Laboratory, San Diego, CA). For each assay, cell
extract (20 µl) was added into a cuvette, and the reaction was
started by injection of 100 µl luciferase substrate. Each reaction
was measured for 10 sec in the Luminometer. Luciferase activity was
defined as light units per mg protein.
Mammalian One-Hybrid Assay
Mammalian one-hybrid assay was performed to determine
transcription factor Sp1 and AR interaction. Transcription factor Sp1
was used as bait. Artificial coactivators are fusion proteins that
contain either full-length AR or the ligand-binding domain of AR fused
with transactivation domain from either viral protein 16 (VP16) or
mammalian transcription factor p65/RelA.
Coimmunoprecipitation Assay
Nuclear extracts were prepared from control and androgen-treated
LNCaP-FGC cells. Coimmunoprecipitation was performed in a modified RIPA
buffer (50 mM Tris·Cl (pH 7.5), 1% NP-40, 0.5% sodium
deoxycholate, 0.1% SDS, 100 mM NaCl, 1 mM
dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 10
µg/ml of pepstatin, leupeptin, and aprotinin each). The antibody and
protein complexes were precipitated by Protein G plus/protein A agarose
beads (Calbiochem, San Diego, CA) at 2500 rpm for 5 min.
The beads were washed with the modified RIPA buffer four times. The
protein complexes were subjected to Western blot analysis using
anti-Sp1 or anti-AR antibody, respectively.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by NIH Postdoctoral Fellowship 1 F32 CA-80333–01, NIH Grant R29 CA-78355, and the Department of Veterans Affairs.
Received for publication October 22, 1999. Revision received January 18, 2000. Accepted for publication February 7, 2000.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Long. G. Wang, L. Ossowski, and A. C. Ferrari Overexpressed Androgen Receptor Linked to p21WAF1 Silencing May Be Responsible for Androgen Independence and Resistance to Apoptosis of a Prostate Cancer Cell Line Cancer Res., October 1, 2001; 61(20): 7544 - 7551. [Abstract] [Full Text] [PDF]
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D. K. Lee, H. O. Duan, and C. Chang Androgen Receptor Interacts with the Positive Elongation Factor P-TEFb and Enhances the Efficiency of Transcriptional Elongation J. Biol. Chem., March 23, 2001; 276(13): 9978 - 9984. [Abstract] [Full Text] [PDF]
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E. J. Cram, B. D. Liu, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol Inhibits CDK6 Expression in Human MCF-7 Breast Cancer Cells by Disrupting Sp1 Transcription Factor Interactions with a Composite Element in the CDK6 Gene Promoter J. Biol. Chem., June 15, 2001; 276(25): 22332 - 22340. [Abstract] [Full Text] [PDF]
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E. Castro-Rivera, I. Samudio, and S. Safe Estrogen Regulation of Cyclin D1 Gene Expression in ZR-75 Breast Cancer Cells Involves Multiple Enhancer Elements J. Biol. Chem., August 10, 2001; 276(33): 30853 - 30861. [Abstract] [Full Text] [PDF]
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