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Department of Cell Biology (S.L., M.L., S.Y.T., M.-J.T.) and Department of Medicine (D.E.E., M.-J.T.) Baylor College of Medicine Houston, Texas 77030
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Androgens, acting through their receptors (ARs), are essential for the maintenance of prostatic epithelial cell proliferation and differentiation during development (19). The rates of epithelial cell growth and death in adult prostate glands are in equilibrium, such that there is no net change in cell growth. In an adult rat, the glandular epithelial cells constitute approximately 80% of the total cells in the ventral prostate, and approximately 70% of these cells die by 7 days postcastration (20, 21). The molecular mechanisms of the androgen-mediated maintenance of the integrity of prostatic epithelial cells have not been elucidated and remains an area of active research.
There are many androgen-regulated genes (22). However, only a few of the genes, such as PSA and KLK-2 (23), C(3) protein (24), Slp (25), and probasin (26), have been well characterized, and androgen response elements (AREs) in these genes were identified. Whether these characterized genes are involved in mitogenic signaling of androgen is still unknown. In studying the molecular mechanisms of androgen action on cell growth, we were the first to demonstrate that androgen stimulates the expression of cell cycle genes CDK2 and CDK4 and represses the expression of CDK inhibitor p16 gene, resulting in increased CDK kinase activities (27). Those studies revealed a new class of androgen target genes. In addition, those observations suggested a possible signaling pathway by which androgen stimulates prostate cell growth. In the current study, we identified the CDK inhibitor, p21, as a target gene of androgen. Androgen induces the expression of the p21 gene in prostate cancer cells through an ARE in the proximal p21 promoter.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, the
level of p21 mRNA in LNCaP-FGC cells was increased after 2 h of
treatment with the AR agonist R1881 (10-8 M)
and continued to increase thereafter up to 48 h. In contrast, no
detectable p21 mRNA was observed in androgen-independent PC-3 cells.
The enhancement of p21 expression is specific, since the expressions of
CDK inhibitor p27 (KIP 1) is not altered in response to androgen
stimulation in both LNCaP-FGC and PC-3 cells. We also found that p21
protein levels in LNCaP-FGC cells, as measured by Western blot
analysis, increased in response to R1881 within 8 h (Fig. 1B).
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). It is possible that this phenomenon is due to an enhanced
p21 mRNA stability stimulated by cycloheximide by an unknown mechanism.
We next did nuclear run-on assays to determine whether androgen
directly stimulates p21 gene transcription. As shown in Fig. 1D, we
found an enhanced mRNA synthesis in the RNA preparation isolated from
R1881-treated nuclei as compared with the RNA isolated from control
nuclei. As a control, glyceraldehyde 3-phosphate dehydrogenase
(GAPDH) expressions are similar between control and R1881-treated
sample.
To examine whether androgen directly up-regulates the expression
of the p21 gene, transient cotransfection experiments were performed.
An AR expression vector (CMV-AR) and a reporter construct
(p21(-2400)-Luc) containing 2.4 kb of the p21 promoter fused to a
luciferase reporter were cotransfected into COS 1 cells. Subsequently,
the reporter luciferase activity in response to androgen stimulation
was determined. AR agonist R1881 (10-8 M)
induces an approximately 2-fold increase in luciferase activity in COS
1 cells cotransfected with the p21(-2400)-Luc and cytomegalovirus
(CMV)-AR vectors (Fig. 2A). There is no
increase in luciferase activity upon androgen stimulation in COS 1
cells transfected with p21(-2400)-Luc vector without the AR expression
vector. This result suggests that the COS 1 cells contain no, or low
levels of, endogenous AR. As a control, a reporter construct,
RARE-tk-Luc, which contains two copies of retinoic acid response
element (RARE) fused upstream of the minimal thymidine kinase (tk)
promoter, fails to respond to R1881 when cotransfected with AR
expression vector in COS 1 cells. Since these experiments were carried
out in the COS 1 cell line, which is monkey kidney cells, the results
may not reflect the physiological condition. Thus, these experiments
were also carried out in prostatic carcinoma LNCaP-FGC cells, which
contain a high expression level of a gain-of-function mutated
form of endogenous AR. Figure 2 showed that an increased expression of
luciferase activity was also observed in LNCaP-FGC cells transfected
with p21(-2400)-Luc vector alone in response to R1881 (Fig. 2B). These
results indicate that androgen-dependent induction of luciferase
reporter gene expression is specifically mediated by AR, and a
functional ARE is likely to reside in the 2.4-kb fragment of the
p21 promoter.
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). COS 1 cells were used for transient
transfection experiments by cotransfecting these p21 deletion
constructs and CMV-AR expression vector. As shown in Fig. 3A, the
constructs p21(-2400)-Luc, p21(-1800)-Luc, p21(-600)-Luc, and
p21(-215)-Luc, which include 2.4 kb, 1.8 kb, 0.6 kb, and 0.215 kb of
the p21 promoter fragment, respectively, showed an increased promoter
activity upon androgen stimulation. In contrast, the construct
p21(-60)-Luc, which contains only 60 bp of the p21 gene promoter,
fails to respond to androgen. These results strongly suggested that the
p21 promoter spanning from nucleotides -215 to -60 contains a
functional ARE. A dose-dependent induction of the expression of
luciferase reporter gene driven by 215 bp of the p21 promoter fragment
by varying concentrations of R1881 showed that a concentration as low
as 10-11 M can stimulate the reporter gene
expression (Fig. 3B). The dose-response curve reached a plateau at
concentrations higher than 10-10 M of R1881,
implying that all binding sites have been saturated. A similar
dose-response curve was obtained by transfecting only the reporter
construct p21(-215)-Luc into LNCaP-FGC cells with R1881
EC50 at approximately 5 x 10-11
M (data not shown).
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). Therefore, a
double-stranded oligonucleotide containing the putative ARE sequence
corresponding to the region from nucleotides -215 to -186 of the p21
gene promoter was used in an electrophoretic mobility shift assay
(EMSA) to determine whether AR can bind to this sequence. Figure 4B
showed that the binding of AR to the oligo probe can be supershifted by
anti-AR antibody but not by a nonspecific rabbit IgG, suggesting that
AR binds specifically to the oligo probe. Unlabeled wild-type
oligonucleotide duplexes including AREs from the p21 gene and C(3) gene
could compete efficiently for the binding of AR to the ARE in the p21
gene, indicating that binding is specific. To further support that the
binding is specific, multiple ARE mutants were generated by changing
the conserved nucleotides of the p21 gene ARE as shown in Fig. 4A.
EMSAs showed that there is no specific binding of AR to mutant-2 ARE
and a drastic decrease in AR binding to mutant-3 ARE as compared with
the efficient binding of AR to the wild-type ARE (Fig. 5A). Similarly, the specific binding of
AR to the wild-type ARE can be competed for the unlabeled wild-type ARE
oligo probe of the p21 gene but not by the unlabeled mutant-2 ARE (Fig. 5B). These results collectively indicate that mutation of more than one
conserved nucleotide in the ARE decreases or abolishes the binding by
AR.
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NF1-Luc vector
containing the human tissue transglutaminase gene minimal promoter
(-32 
+5 nucleotides). The resulting constructs are
ARE-TATA-Luc and AREmut-TATA-Luc vectors, respectively (Fig. 6) (28). Transient transfection of these
reporter vectors into LNCaP-FGC cells in the presence or absence of
R1881 demonstrated that only the wild-type ARE, but not the mutated
ARE, can confer the androgen responsiveness to the minimal promoter of
the human tissue transglutaminase gene (Fig. 6). In conclusion, these
results further support the notion that the ARE found in the p21 gene
is authentic.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-74 bp position
of the p21 promoter (30). By inhibiting cell growth in response to
epidermal growth factor and interferon-
treatment, the p21
gene can be up-regulated through STAT1 (signal transducers and
activators of transcription). Three STAT-inducible elements (SIEs) in
the promoter of the p21 gene were identified, which are located at
-640, -2540, and -4183 bp (31). A functional p53-RE was also located
at approximately 2.4 kb upstream of the p21 gene-coding region (11). It
has also been demonstrated that the E2A gene products, E12 and E47, can
up-regulate the p21 gene expression through two E boxes in the proximal
p21 promoter to suppress cell growth (32). Here we demonstrated that
androgen transcriptionally regulates the expression of the p21 gene.
Our studies thus reveal a cross-talk of cell cycle control and androgen
action at the molecular level. Determination of the biological functions ascribed to p21 suggests that p21 is a multifunctional protein playing a key role in the cell cycle control, DNA repair, and antiapoptosis (33, 34, 35). When one p21 molecule binds to one cyclin-CDK complex, the resulting complex is active and can phosphorylate Rb to allow cell cycle to progression. When two or more p21 molecules bind per cyclin-CDK complex, kinase activities are inhibited, and cell cycle progression is blocked. p21 is known to inhibit proliferating-cell nuclear antigen in DNA replication but not in DNA repair, leading to the inactivation of chromosomal replication while allowing DNA damage-responsive repair (36). In addition, it has been shown that during terminal differentiation of myocytes, p21 induction is correlated with the acquisition of an apoptotic-resistant phenotype (34). p21 Is also required for the survival of differentiating neuroblastoma cells (37). More direct evidence is that p21 protects against p53-mediated apoptosis of human melanoma cells (35). Furthermore, a transcriptionally incompetent p53 can induce apoptosis, but not growth arrest, whereas induction of p21, which is a major transcriptional target of p53, can induce growth arrest but not apoptosis (38). Therefore, this evidence suggests that p21 plays a major role in cell proliferation, differentiation, and apoptosis.
To investigate the molecular mechanisms in the development of androgen-independent growth of prostate cancer, we have established an androgen-independent prostatic carcinoma cell line LNCaP-AI by culturing the parental androgen-dependent LNCaP-FGC cell line in medium containing stripped serum. It is interesting to find that there is a drastic increase in the basal expression of the p21 gene in this androgen-independent cell line, although the cells can grow very well in the absence of androgen (S. Lu, S. Tsai, and M.-J. Tsai, unpublished observation). Androgen is essential for the maintenance of the integrity of the prostatic epithelium, and androgen withdrawal results in massive apoptosis of the prostatic epithelial cells and prostate evolution. bcl-2 Was demonstrated to be involved in the development of androgen-independent growth (39, 40). In normal prostatic secretory epithelial cells, there are no detectable levels of bcl-2 expression. The correlation between the up-regulation of the p21 gene and acquisition of androgen-independent cell growth led us to speculate that in the normal prostatic epithelial cells, up-regulation of p21 gene by androgen may play an antiapoptotic role in an androgen-dependent manner but not an inhibitory role in cell cycle progression.
p21 Is the fourth androgen-regulated cell cycle gene we have identified. To investigate the molecular mechanisms of androgen induction of p21 expression, we have performed detailed functional analyses on the p21 promoter. By deletion and mutation analyses, we have defined a consensus ARE sequence located at -200 bp of the p21 promoter that is required for androgen-activated transcription. EMSA with the wild-type and mutated ARE sequences of the p21 gene using nuclear extracts from LNCaP-FGC cells revealed one specific band of retarded mobility, which can be supershifted by anti-AR antibody. The presence of this retarded band is correlated functionally with the ability of the ARE to drive androgen-mediated transcription to a heterologous promoter.
Recent studies have demonstrated that a glucocorticoid response element (GRE)- or progesterone response element (PRE)-like element with consensus sequence 5'-GGA/TACAnnnTGTTCT-3' functions as ARE, which may be due to the homologous properties between AR, GR, and PR. However, AREs in Slp and probasin genes exhibit preference for AR (25, 26). According to the characteristics of the identified ARE, some of them are simple ARE, which typically consists of an imperfect palindrome sequence with a 3-bp spacer between the two half-sites. The examples are the AREs in PSA and hKLK2 genes (23, 41). There are also complex AREs in which multiple elements and the binding of multiple proteins to these elements are required for full androgen-induced activity. These are exemplified in AREs in Slp and probasin genes (25, 26). For the ARE in the p21 gene, it appears to be a simple ARE element.
In summary, our studies show convincingly that androgen acts on the p21 gene. This finding points to an interesting possibility that the CDK inhibitor p21 may be involved in the androgen-mediated antiapoptotic function in the prostatic epithelial cell. Further studies are currently underway to investigate this hypothesis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Reagents
R1881 was purchased from Dupont Biotechnology Systems (Boston,
MA). Human p27 and p21 cDNA probes were kindly provided by Dr. Wade
Harper (Department of Biochemistry, Baylor College of Medicine). The
vector RARE-tk-Luc was a gift from Dr. Richard Heyman (Ligand, La
Jolla, CA). Anti-AR antibody was a gift from Dr. Nancy Weigel
(Department of Cell Biology, Baylor College of Medicine).
Northern Blot Analysis
Total cellular RNAs from control and R1881-treated samples were
isolated using Ultraspec RNA isolation reagent (Biotecx Laboratories,
Inc., Houston, TX). Total RNA (20 µg/sample) was fractionated on a
1% formaldehyde agarose gel and transferred onto a nylon filter
(Hybond-N, Amersham Life Science, Arlington Heights, IL). Northern
hybridization was performed using Quikhyb hybridization solution
according to the manufacture’s recommendations (Stratagene, La Jolla,
CA). Quantitation of each band was performed using ScanAnalysis
computer program (BIOSOFT, Ferguson, MO).
Western Blot Analysis
Aliquots of samples with same amount of protein,
determined using the Bradford assay (Bio-Rad, Hercules, CA), were mixed
with loading buffer [final concentrations of 62.5 mM
Tris-HCl (pH 6.8), 2.3% SDS, 100 mM dithiothreitol, and
0.005% bromophenol blue], boiled, fractionated in a 15% SDS-PAGE,
and transferred onto a 0.45-µm nitrocellulose membrane (Bio-Rad). The
filters were blocked with 2% fat-free milk in PBS and probed with
anti-CDK2 and anti-CDK4 antibodies (0.05 µg/ml IgG) (Santa Cruz
Biotechnology, Santa Cruz, CA) in PBS containing 0.1% Tween 20 (PBST)
and 1% fat-free milk. The membranes were then washed once in PBST and
incubated with horseradish peroxidase-conjugated F(ab')2 of
goat antirabbit secondary antibody (Bio-Rad) in PBST containing 1%
fat-free milk. After washing four times in PBST, the membranes were
visualized using the enhanced chemiluminescence (ECL) Western blotting
detection system (Amersham Life Science). Quantitation of each band was
performed using ScanAnalysis computer program (BIOSOFT).
Nuclear Run-on Assay
LNCaP-FGC cells were cultured in medium containing 10% stripped
serum for 1 week. Nuclei were isolated from approximately 5 x
107 of either control cells or cells treated overnight with
R1881. Cells were lysed twice in NP-40 lysis buffer [10 mM
Tris-Cl (pH 7.4), 10 mM NaCl, 3 mM
MgCl2, and 0.5% NP-40] by incubating on ice for 5 min
each time, and obtained nuclei were frozen at -80 C in 100 µl of
glycerol storage buffer [50 mM Tris-Cl (pH 8.3), 40%
(vol/vol) glycerol, 5 mM MgCl2, 0.1
mM EDTA]. To perform nuclear run-on transcription, the
frozen nuclei were thawed at room temperature. One hundred microliters
of 2x reaction buffer with nucleotides [10 mM Tris-Cl (pH
8.0), 5 mM MgCl2, 0.3 M KCl, 1
mM ATP, 1 mM CTP, 1 mM GTP, and 5
mM DTT] plus 10 µl of 10 mCi/ml
[
-32P]UTP were added. The reaction was incubated 30
min at 30 C with shaking. The nuclei were spun 5 min at 500 x
g and 4 C. RNAs were isolated using Ultraspec RNA isolation
reagent (Biotecx Laboratories, Inc.). For hybridization, 500 ng of
denatured p21 or GAPDH cDNA was used for each dot slot of Zeta-probe
membrane (Bio-Rad). The dot-slot strips were prehybridized in Quick-hyb
hybridization solution (Stratagene) for 3 h at 68 C. Subsequently,
2 x 106 cpm/ml denatured RNA probe were added and
hybridization was performed for 24 h at 68 C. The strips were
washed twice in 2x saline sodium citrate (SSC) and 0.1% SDS at
room temperature for 15 min and once in 0.2x SSC and 0.1% SDS at 50 C
for 15 min followed by x-ray exposure.
Transient Transfection Assay
COS 1 cells (105) or 2 x 105
LNCaP-FGC cells were seeded in six- well tissue culture plates. Next
day, lipofectin-mediated transfection was used for the transient
transfection assays according to the protocol provided by Life
Technologies, Inc.. Cell extracts were prepared according to in
vitro luciferase assay kit (Promega, 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/mg protein.
EMSA
EMSA was carried out as described in a bandshift assay
system (Promega). Nuclear extract isolated from LNCaP-FGC cells treated
with R1881 was used. The oligo probe containing p21-ARE is
AAGCTTAGTACGTGATGTTCTAAGCTT. The probes
containing mutated AREs are shown in Fig. 4A.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by Baylor Specialized Program of Research Excellence in prostate cancer (CA-58204).
Received for publication June 25, 1998. Revision received October 28, 1998. Accepted for publication November 30, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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D. Waltregny, I. Leav, S. Signoretti, P. Soung, D. Lin, F. Merk, J. Y. Adams, N. Bhattacharya, N. Cirenei, and M. Loda Androgen-Driven Prostate Epithelial Cell Proliferation and Differentiation in Vivo Involve the Regulation of p27 Mol. Endocrinol., May 1, 2001; 15(5): 765 - 782. [Abstract] [Full Text]
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S. Lu, G. Jenster, and D. E. Epner Androgen Induction of Cyclin-Dependent Kinase Inhibitor p21 Gene: Role of Androgen Receptor and Transcription Factor Sp1 Complex Mol. Endocrinol., May 1, 2000; 14(5): 753 - 760. [Abstract] [Full Text]
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S. H. Mitchell, W. Zhu, and C. Y. F. Young Resveratrol Inhibits the Expression and Function of the Androgen Receptor in LNCaP Prostate Cancer Cells Cancer Res., December 1, 1999; 59(23): 5892 - 5895. [Abstract] [Full Text] [PDF]
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S. Lu, S. Y. Tsai, and M.-J. Tsai Molecular Mechanisms of Androgen-Independent Growth of Human Prostate Cancer LNCaP-AI Cells Endocrinology, November 1, 1999; 140(11): 5054 - 5059. [Abstract] [Full Text]
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H.-K. Lin, S. Yeh, H.-Y. Kang, and C. Chang Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor PNAS, June 19, 2001; 98(13): 7200 - 7205. [Abstract] [Full Text] [PDF]
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S. Yeh, Y.-C. Hu, M. Rahman, H.-K. Lin, C.-L. Hsu, H.-J. Ting, H.-Y. Kang, and C. Chang Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells PNAS, October 10, 2000; 97(21): 11256 - 11261. [Abstract] [Full Text] [PDF]
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M. Stanbrough, I. Leav, P. W. L. Kwan, G. J. Bubley, and S. P. Balk Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium PNAS, September 11, 2001; 98(19): 10823 - 10828. [Abstract] [Full Text] [PDF]
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-Probe strips containing 500 ng of either p21 cDNA or
GAPDH cDNA on each dot slot were used for hybridization probed by
labeled RNA from both control and R1881-treated cells.
