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Advances in Brief |
Ludwig Institute for Cancer Research [K. E. K., W. K. C., K. C. A.], Department of Medicine [W. K. C., K. C. A.], Center for Molecular Genetics [W. K. C.], and Cancer Center [W. K. C.], University of California at San Diego, La Jolla, California 92093-0660; and University of Cincinnati School of Medicine, Department of Cell Biology, Cincinnati, Ohio 45267-0521 [K. E. K.]
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ABSTRACT |
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Introduction |
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Recent evidence also points to a direct role for D-type cyclins in transcriptional activation and repression. For example, it has been shown that cyclin D1 inhibits transcriptional activation by the DMP1 transcription factor (4) . Conversely, a multitude of evidence now shows that cyclin D1 binds the estrogen receptor and activates its transactivation potential in a ligand-independent manner (2 , 3) . In both cases, the influence of cyclin D1 on transcription has been shown to occur independently of its role in cell cycle progression, thus defining a novel function for D-type cyclins as transcriptional regulators.
Prostatic epithelial cells are dependent on specific steroidal hormones for proliferation, and this dependency is commonly lost in prostatic adenocarcinoma cells (7 , 8) . Growth of normal prostate cells is dependent on the presence of androgen, which elicits its biological activity via the androgen receptor, a member of the nuclear steroid hormone receptor family (9) . DHT is a high-affinity ligand for the androgen receptor, and upon DHT binding, the transcriptional transactivation potential of the androgen receptor is activated (9) . Upon activation, the androgen receptor stimulates the transcription of a number of target genes. Although many of these target genes have yet to be identified, the best characterized to date is that encoding PSA (9) . PSA expression correlates well with active androgen receptors and the growth of prostate cells and, as such, is used clinically as a measure of prostate growth (10) . We have previously shown that D-type cyclins play a key regulatory role in the androgen-dependent proliferation of prostate cells (11) . To test whether D-type cyclins influence the transactivation potential of the androgen receptor, we investigated the effects of D-type cyclins on the androgen receptor using the PSA promoter as a reporter of androgen receptor function. Surprisingly, we found that D-type cyclins repress activation of androgen receptor-mediated transcription and do so in a direct, cell cycle-independent manner. These findings may explain the low frequency of cyclin D1 amplification in prostatic adenocarcinomas.
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Materials and Methods |
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Transcriptional Activation Assays.
CV1 and SAOS-2 cells were transfected with the indicated plasmids using the N,N-bis(2-hydroxyethyl)-2-amino-ethanesulfonic acid/calcium phosphate method (12)
in 60-mm dishes using 8 µg of total DNA per transfection. Approximately 16 h posttransfection, cells were washed with PBS and replaced in phenol red-free DMEM-10% charcoal dextran-treated fetal bovine serum with or without 0.1 nM R1881 (DuPont/NEN, Boston, MA), a DHT analogue. Approximately 30 h later, cells were harvested and luciferase activity was monitored using commercially available reagents (Promega, Madison, WI). ß-Galactosidase activity was also monitored as an internal control for transfection efficiency.
Plasmids.
The CMV-ß-galactosidase, CMV-CDK4, and CMV-cyclin A constructs were gifts of Dr. Jean Wang (University of California at San Diego, La Jolla, CA). The pAR0 human androgen receptor construct was a gift of Dr. A. O. Brinkmann (Erasmus Universiteit, Rotterdam, the Netherlands), and the pSG5-AR androgen receptor expression construct was a gift of Dr. Chawnshang Chang (University of Rochester, Rochester, NY). The PSA61LUC reporter construct, which contains 6.1 kb of the human PSA promoter, was a gift of Dr. Kitty Cleutjens (Erasmus Universiteit; Ref. 13
). The dominant negative androgen receptor constructs pSG5-rAR
46–408 and pSG5-rAR38–296 were provided by J. Palvimo and O. Janne (University of Helsinki, Helsinki, Finland; Ref. 14
). The RSV-cyclin D1 and RSV-cyclin D3 constructs were kindly provided by Dr. C. Sherr (St. Jude Children’s Research Hospital, Memphis, TN). The pRcCyclin D1-GH and pRcCyclin D1-KE constructs were gifts of Dr. Robert Weinberg (Whitehead Institute for Biomedical Research, Cambridge, MA). The cyclin E expression construct (expressed from a long terminal repeat) was obtained from Dr. J. Roberts (Fred Hutchinson Cancer Research Center, Seattle, WA).
Immunoprecipitation and Immunoblots.
CV1 cells were cultured in 10-cm dishes and cotransfected with 8 µg of pAR0 and 8 µg of RSV-cyclin D1. Approximately 48 h posttransfection, cells were harvested and lysed in NETN [20 mM Tris (pH 8.0), 100 mM NaCl, 1 mM EDTA (pH 8.0), and 0.5% NP40] supplemented with 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml 1,10-phenanthroline, 10 µg/ml aprotinin, 10 µg/ml leupeptin, 10 mM sodium fluoride, 1 mM sodium vanadate, and 60 mM ß-glycerophosphate. Following brief sonication and clarification, lysates were subjected to immunoprecipitation with antisera against MDM2 (Santa Cruz Biotechnology, Santa Cruz, CA), the androgen receptor (Santa Cruz Biotechnology), cyclin E (Santa Cruz Biotechnology), cyclin A (Santa Cruz Biotechnology), or cyclin D1 (Santa Cruz Biotechnology). Immunoprecipitates were recovered using protein A-Sepharose (Pharmacia) and were subjected to 10.5% SDS-PAGE. For immunoprecipitates from cells transfected with cyclin D1 and the androgen receptor, following transfer to Immobilon (Millipore), the membrane was split at the Mr 50,000 marker, the top half was probed using the anti-androgen receptor antibody, and the lower half was probed using the anti-cyclin D1 antibody. For immunoprecipitates from cells transfected with cyclin A and the androgen receptor, following transfer to Immobilon (Millipore), samples were run in duplicate to probe for cyclin A and the androgen receptor. Proteins were visualized using horseradish peroxidase-conjugated protein A (Bio-Rad) and enhanced chemiluminescence (Amersham).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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In CV1 cells, introduction of PSA61LUC resulted in only low-level background luciferase activity in the presence or absence of R1881 (Fig. 1A)
, as was expected, based on our observation that no endogenous androgen receptor can be detected in these cells (data not shown). These results also confirm that activation of the PSA promoter is specific to introduction of an activated androgen receptor. Likewise, CV1 cells transfected with the androgen receptor (pAR0 or pSG5-AR) but maintained in a steroid-free environment also demonstrated only low-level PSA61LUC activity (Fig. 1A)
. By contrast, cells transfected with the androgen receptor and empty vector RcRSV, and treated posttransfection with R1881 demonstrated a significant (5–10-fold) increase in PSA61LUC activation. Strikingly, we observed that cotransfection of RSV-cyclin D1 at a 3:1 ratio with the androgen receptor resulted in a dramatic inhibition of PSA61LUC activation (Fig. 1A)
. This reduced androgen receptor transactivation potential was observed with both the pAR0 and pSG5-AR constructs. Interestingly, cyclin D1 specifically inhibited the ligand dependent activity of PSA61LUC and not the basal activity.
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, cyclin D-mediated inhibition of androgen receptor activation could be observed at a 1:1 ratio (2-fold decrease), was more pronounced at a 1:3 ratio (3-fold decrease), and forced measurable PSA61LUC activity to below background at a 1:5 ratio.
To determine whether this transcriptional modulation was specific to cyclin D1 or whether it was a function of cyclins in general, CV1 cells were cotransfected with cyclin D1, E, or A at a 1:3 ratio of cyclin to androgen receptor. As seen in Fig. 1C
, PSA61LUC activation was not significantly affected by cotransfection with cyclin E or A but was inhibited by cyclin D1. All cyclin constructs have been previously shown to encode functional cyclin gene products (11)
. Therefore, inhibition of androgen receptor transactivation potential was not mediated by cyclin E or cyclin A but was mediated by cyclin D1. To determine whether this function of cyclin D1 was common to the D-type cyclin family, similar experiments were performed using cyclin D3. As shown in Fig. 1D
, cyclin D3 was also capable of inhibiting PSA61LUC activation, albeit to a lesser extent than cyclin D1. These results indicate that the ability to inhibit androgen-mediated receptor transactivation potential was shared by specific members of the D-type cyclin family.
Several classes of proteins have been reported to repress the transactivation function of the androgen receptor. Among these are dominant negative androgen receptor proteins, which lack transactivation potential and prevent transactivation from wild-type receptors by heterodimerization (14)
. We compared the transcriptional antagonistic activities of two such mutant proteins, AR38–296 and AR46–408, with that exhibited by cyclin D1. At equivalent ratios of androgen receptor:effector, all three inhibitory proteins reduced PSA61LUC activation to just above background levels (Fig. 2)
. Therefore, transcriptional inhibition associated with cyclin D1 was similar to that observed using known dominant negative androgen receptor proteins.
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. These data indicate that this attribute of cyclin D1 was independent of its role in cell cycle progression.
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, these mutants of cyclin D1 were able to suppress PSA61LUC activation as effectively as wild-type cyclin D1, again suggesting that this function of cyclin D1 was independent of its cell cycle role. As such, it would be predicted that cyclin D1 may bind to proteins other than CDK4 to carry out this function, and so CDK4 could potentially then compete for this function of cyclin D1. To test this, we cotransfected CDK4 along with cyclin D1 and the androgen receptor (3:3:1 ratio, respectively) and monitored reporter activity. Strikingly, cotransfection of CDK4 was able to partially restore the PSA61LUC activation that was inhibited in the presence of cyclin D1 alone (Fig. 3C)
. In addition, cotransfection of dominant-negative, kinase-defective CDK4 also partially restored PSA61LUC activation. Taken together, the data in Fig. 3
suggest that cyclin D1 inhibited androgen-mediated receptor transactivation potential in a cell cycle-independent manner. Moreover, the data in Fig. 3C
suggest that the cyclin D1 complexes required for transcriptional squelching may be distinct from CDK4-containing complexes.
Cyclin D1 Interacts Directly with the Androgen Receptor.
Because of these observations and because of the functional relationship we observed between cyclin D1 and the androgen receptor, we questioned whether these two proteins may physically interact. To test this, we cotransfected CV1 cells at equal ratios with androgen receptor and cyclin D1 expression plasmids. Transfected cells were lysed, and protein complexes were recovered using antisera generated against either cyclin D1, the androgen receptor, or MDM2 (negative control). Immunoprecipitated complexes were subjected to SDS-PAGE and immunoblotted for either the androgen receptor or cyclin D1. As can be seen in Fig. 4A
, complexes immunoprecipitated using anti-cyclin D1 antisera contained both cyclin D1 and the androgen receptor. Conversely, complexes immunoprecipitated using anti-androgen receptor antisera contained both the androgen receptor and cyclin D1 proteins. Lysates immunoprecipitated using anti-MDM2 antisera failed to recover either cyclin D1 or the androgen receptor. To further verify the specificity of this interaction, CV1 cells were cotransfected with expression constructs for cyclin A and the androgen receptor, and similar immunoprecipitation experiments were performed. As can be seen in Fig. 4B
, immunoprecipitates recovered using anti-androgen receptor antisera contained only the androgen receptor protein and not cyclin A. Conversely, immunoprecipitates recovered using anti-androgen receptor antisera contained only the cyclin A protein and not the androgen receptor. Lysates immunoprecipitated using anti-cyclin E antisera also failed to recover either cyclin A or the androgen receptor (Fig. 4B)
. Thus, cyclin D1 forms a specific complex with the androgen receptor.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. The intensity of androgen receptor transcriptional inhibition was comparable to that observed with known dominant negative androgen receptors (Fig. 2)
. The ability to inhibit PSA61LUC transactivation was shared with cyclin D3, but not with cyclin E or cyclin A (Fig. 1)
. Interestingly, the ability of cyclin D1 to limit androgen receptor transactivation potential was shown to be independent of the cell cycle role of cyclin D because transcriptional repression was observed in cells that are refractory to the growth-promoting effects of cyclin D1 and with mutants of cyclin D1 that are defective for binding to CDK4 or RB (Fig. 3)
. Also, the effect of cyclin D1 on PSA61LUC transactivation could be partially competed by overexpression of CDK4 or kinase-defective CDK4 (Fig. 3)
. Finally, we observed a specific, direct interaction between cyclin D1 and the androgen receptor, suggesting that the effect of cyclin D1 on androgen-dependent transactivation is direct (Fig. 4)
. Our finding that cyclin D1 inhibits the transactivation potential of the androgen receptor directly contrasts with its ability to activate another steroid hormone receptor, the estrogen receptor, in a ligand-independent manner (2 , 3) . The finding that factors/proteins that act as a coactivators for one nuclear receptor act as corepressors for another receptor is not unprecedented. For example, the coactivator SRC-1 enhances transcriptional activity of many steroid hormone receptors (e.g., estrogen, progesterone, and glucocortocoid receptors) but represses transcriptional activity of the androgen receptor (18) . Breast epithelial cells are dependent on estrogen for growth and, consequently, antiestrogens (e.g., 4-hydroxytamoxifen) are relied upon to treat breast carcinoma (19) . Because amplification or overexpression of cyclin D1 is observed in >50% of breast carcinomas, this may provide the means for breast cancer cells to bypass the estrogen requirement (5 , 20) . Consistent with this and unlike estrogen-mediated activation, cyclin D1-induced activation of the estrogen receptor is only slightly perturbed by 4-hydroxytamoxifen (2 , 3) . These studies underscore the importance of understanding how hormone-dependent cells regulate the requirement for steroids and how cancer cells evade this requirement.
The studies presented here point to an important role for cyclin D1 in regulating the transactivation potential of the androgen receptor. We have previously shown that, in LNCaP cells, which are dependent on androgen for growth, a decrease in D-type cyclin expression is observed upon androgen withdrawal (11) . Conversely, such cells cultured in the presence of androgen demonstrate high levels of D-type cyclin expression and associated kinase activity (11) . On the basis of the studies presented here, we propose that a negative feedback loop may exist in androgen-dependent prostate cells, wherein ligand-dependent activation of the androgen receptor results in stimulation of cyclin D expression. This net increase in cyclin D would promote cell cycle progression but may also act to attenuate the transcriptional activity of the androgen receptor, thus modulating the rate of future cell cycle progression. This hypothesis may explain the biphasic response of prostate cells to androgen (21) , wherein androgen-dependent prostate cells undergo growth arrest either in the absence of androgen (i.e., in the absence of cyclin D) or in the presence of excess androgen (i.e., in the presence of excess cyclin D).
Deregulation of cell cycle control is a common component of cancer. Specifically, the RB/cyclin D1/p16ink4a pathway is targeted for disruption in >60% of studied tumors (1 , 22) . Typically, the mutations that target this pathway are tumor type specific (1 , 5 , 23) . For example, in small cell lung carcinoma, RB is commonly inactivated, whereas in non-small cell lung carcinoma, p16ink4a is lost. The basis behind this specificity is largely not understood. The finding that cyclin D1 synergizes with the estrogen receptor indicates that the frequent amplifications of cyclin D1 in breast cancer confer a specific growth advantage both through ubiquitous activation of CDK4 and through activation of the estrogen receptor. Our finding that cyclin D1 subverts androgen receptor signaling provides an explanation for why cyclin D1 amplifications are not commonly observed in prostate carcinomas, whether they are androgen dependent or androgen independent (24) . In contrast, inactivating mutations of RB are frequently observed in prostate carcinomas (25) . Together, these findings may help explain the cell type specificities of the mutations of the RB/cyclin D1/p16ink4a pathway observed in human breast versus prostate carcinomas.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 K. E. K. is supported by a National Research Service Award from NIH (Grant CA82034). 
2 To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA 92093-0660. Phone: (619) 534-7812; Fax: (619) 534-7802; E-mail: karden{at}ucsd.edu
3 The abbreviations used are: CDK, cyclin-dependent kinase; DHT, dihydrotestosterone; PSA, prostate-specific antigen; CMV, cytomegalovirus; RSV, Rous sarcoma virus.
Received 1/28/99. Accepted 3/30/99.
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E. A. Musgrove, L.-J. K. Hunter, C. S. L. Lee, A. Swarbrick, R. Hui, and R. L. Sutherland Cyclin D1 Overexpression Induces Progestin Resistance in T-47D Breast Cancer Cells Despite p27Kip1 Association with Cyclin E-Cdk2 J. Biol. Chem., December 7, 2001; 276(50): 47675 - 47683. [Abstract] [Full Text] [PDF]
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S. L. Holley, G. Parkes, C. Matthias, U. Bockmuhl, V. Jahnke, K. Leder, R. C. Strange, A. A. Fryer, and P. R. Hoban Cyclin D1 Polymorphism and Expression in Patients with Squamous Cell Carcinoma of the Head and Neck Am. J. Pathol., November 1, 2001; 159(5): 1917 - 1924. [Abstract] [Full Text] [PDF]
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 I. Bieche, B. Parfait, S. Tozlu, R. Lidereau, and M. Vidaud Quantitation of androgen receptor gene expression in sporadic breast tumors by real-time RT-PCR: evidence that MYC is an AR-regulated gene Carcinogenesis, September 1, 2001; 22(9): 1521 - 1526. [Abstract] [Full Text] [PDF]
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P. L. Miliani de Marval, I. B. Gimenez-Conti, M. LaCava, L. A. Martinez, C. J. Conti, and M. L. Rodriguez-Puebla Transgenic Expression of Cyclin-Dependent Kinase 4 Results in Epidermal Hyperplasia, Hypertrophy, and Severe Dermal Fibrosis Am. J. Pathol., July 1, 2001; 159(1): 369 - 379. [Abstract] [Full Text] [PDF]
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M. L. Rodriguez-Puebla, M. LaCava, P. L. Miliani de Marval, J. L. Jorcano, E. R. Richie, and C. J. Conti Cyclin D2 Overexpression in Transgenic Mice Induces Thymic and Epidermal Hyperplasia whereas Cyclin D3 Expression Results Only in Epidermal Hyperplasia Am. J. Pathol., September 1, 2000; 157(3): 1039 - 1050. [Abstract] [Full Text] [PDF]
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D. Germain, A. Russell, A. Thompson, and J. Hendley Ubiquitination of Free Cyclin D1 Is Independent of Phosphorylation on Threonine 286 J. Biol. Chem., April 14, 2000; 275(16): 12074 - 12079. [Abstract] [Full Text] [PDF]
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C. E. Petre, Y. B. Wetherill, M. Danielsen, and K. E. Knudsen Cyclin D1: Mechanism and Consequence of Androgen Receptor Co-repressor Activity J. Biol. Chem., January 11, 2002; 277(3): 2207 - 2215. [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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) or were treated with 0.1 nM R1881 (
) for 36 h. After 36 h, cells were harvested, and luciferase activities were measured and normalized against ß-galactosidase activity. Experiments were performed at least in triplicate. Columns, averages; bars, SD. Maximum androgen receptor activity (as exhibited by cells transfected only with CMV-betagal, AR, PSA61LUC, and RcRSV and treated with R1881) was set at 100%. A, androgen receptor transactivation potential is attenuated by cyclin D1. Cells transfected at a 1:3 ratio with either pAR0 or pSG5AR and cyclin D1 demonstrate reduced transactivation potential. B, cyclin D1 attenuates androgen receptor transactivation in a dose-dependent manner. Cells were transfected either in the absence of cyclin or at a 1:1–1:5 ratio of androgen receptor to cyclin. C, attenuation of androgen receptor transactivation is specific to cyclin D. Cells were transfected with either cyclin D1, cyclin A, or cyclin E at the ratios shown. D, transcriptional inhibition is conserved with other D-type cyclins. Cells were transfected with either cyclin D1 and cyclin D3 at the ratios indicated.
