CREB Binding Protein Is a Coactivator for the Androgen Receptor and Mediates Cross-talk with AP-1

Abstract

Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated through the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. In addition to its ability to activate transcription from androgen response elements, AR can inhibit activator protein-1 (AP-1) activity, composed of Jun and Fos oncoproteins, in a ligand-dependent manner. Conversely, when activated, AP-1 can block AR activity. We found that CREB (cAMP response element-binding protein) binding protein (CBP) had a direct role in both of these activities of AR. CBP significantly increased the ability of endogenous AR in LNCaP cells to activate transcription from an AR-dependent reporter construct. On the other hand, repression of AR activity by treatment of LNCaP cells with an activator of AP-1 was largely relieved when CBP was ectopically expressed. AR and CBP can physically interact in vitro as was shown in glutathione S-transferase pulldown assays. Whereas both the N terminus and ligand-binding domain of AR can interact with CBP, a short region in the N terminus of CBP is required for these interactions. As opposed to the interaction of CBP with other nuclear receptors studied so far, CBP-AR interactions were not affected by ligand binding to AR in vitro. These data suggest that CBP is a coactivator for AR in vivo and that the transcriptional interference between AR and AP-1 is the result of competition for limiting amounts of CBP in the cell. Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated through the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. In addition to its ability to activate transcription from androgen response elements, AR can inhibit activator protein-1 (AP-1) activity, composed of Jun and Fos oncoproteins, in a ligand-dependent manner. Conversely, when activated, AP-1 can block AR activity. We found that CREB (cAMP response element-binding protein) binding protein (CBP) had a direct role in both of these activities of AR. CBP significantly increased the ability of endogenous AR in LNCaP cells to activate transcription from an AR-dependent reporter construct. On the other hand, repression of AR activity by treatment of LNCaP cells with an activator of AP-1 was largely relieved when CBP was ectopically expressed. AR and CBP can physically interact in vitro as was shown in glutathione S-transferase pulldown assays. Whereas both the N terminus and ligand-binding domain of AR can interact with CBP, a short region in the N terminus of CBP is required for these interactions. As opposed to the interaction of CBP with other nuclear receptors studied so far, CBP-AR interactions were not affected by ligand binding to AR in vitro. These data suggest that CBP is a coactivator for AR in vivo and that the transcriptional interference between AR and AP-1 is the result of competition for limiting amounts of CBP in the cell. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1.Journal of Biological ChemistryVol. 274Issue 35PreviewPage 31854, under “GST Pulldown Assay”: In the seventh line from the bottom of that paragraph, the composition of a buffer (NETN) is given as “(0.01% Nonidet P-40, 20 mmTris-HCl (pH 8.8), 1 mm EDTA, and 40 mmNaCl.” It should read “(0.01% Nonidet P-40, 20 mmTris-HCl (pH 8.0), 1 mm EDTA, and 40 mmNaCl).” Full-Text PDF Open Access androgen receptor activator protein-1 cAMP response element-binding protein CREB binding protein ligand-binding domain N-terminal domain 12-O-tetradecanoylphorbol-13-acetate 4-morpholineethanesulfonic acid glutathioneS-transferase luciferase activator function androgen response element. Androgens have a pivotal role in the development and maintenance of the male reproductive system (1Quigley C.A. DeBille A. Marschke K.B. El-Awady M.K. Wilson E.M. French F.S. Endocr. 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We found that CBP can the transcriptional activity of endogenous AR in LNCaP is of a direct of CBP, through its N with both the AR NTD and LBD, in assays. Furthermore, that the transcriptional interference between AR and AP-1 may be mediated through competition for limiting amounts of CBP in the cell. LNCaP cells were in which was with and The F. D. B. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar) was for of mm of of was with of mm which the to be were in with of reporter and amounts of CBP or an and to a of of the was to was and cells were with 12-O-tetradecanoylphorbol-13-acetate were and cells were with and in mm and mm and luciferase activities were and (5Ikonen T. Palvimo J.J. Janne O.A. J. Biol. Chem. 1997; 272: 29821-29828Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar) and CBP and M.R. Nature. 1994; PubMed Scopus Google Scholar) have been the of the AR the AR from M. J. French F.S. Wilson E.M. Mol. Endocrinol. PubMed Scopus Google Scholar) was between the and of the of glutathione S-transferase of the AR N terminus and the ligand-binding domain the were by the and The were with and and the in to and the of was with and one of the in with the were to and respectively. the of M.R. Nature. 1994; PubMed Scopus Google Scholar) was the in and was with and either in with and In vitro interactions between AR and CBP were by the pulldown as described F. Lopez G. E. H. A. J. Kushner P.J. J.D. Karin M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). and proteins were expressed in and The proteins were in the or of for they were binding CBP and AR and its were in vitro the in system in the of and were with and in buffer Nonidet P-40, 20 mm (pH 8.8), 1 mm EDTA, and 40 mm the were with in and were and a the role of CBP in AR-dependent in LNCaP reporter in which a of the is to the luciferase (5Ikonen T. Palvimo J.J. Janne O.A. J. Biol. 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LNCaP cells were with in the of either an or an cells were either or with the androgen and cells were and luciferase activities were As shown in 1 in the of was of when the was with the In the of was increased by an CBP was the of in the of increased by In the of reporter increased with that in the of the These data that the CBP activity 1 is not for this reporter and suggest that CBP can function as a coactivator for AR in has an of of transcription by the through the of AP-1 M. F. P. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). CBP was also shown to as a coactivator for J. P. Claret F.X. T. Karin M. J. M. Nature. 1994; PubMed Scopus Google Scholar), a of the AP-1 and it has been as a role in the cross-talk between AP-1 and some nuclear receptors Y. Xu L. Heinzel T. Torchia J. Kurokawa R. Gloss P. Lin S.-C. Heyman R.A. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 1996; 85: 403-414Abstract Full Text Full Text PDF PubMed Scopus (1928) Google Scholar). the of CBP of AR activity. that LNCaP cells were with the reporter construct. cells were either or with cells were and luciferase activities were As shown in treatment increased by and treatment not significantly when cells were with and of the by was when the was in the of an CBP, block of of was to by These data suggest that CBP is in limiting amounts in LNCaP cells and that the ability of to inhibit AR activity from the of CBP by other transcription factors by such as these the was with the LNCaP cells were with the construct. cells were either or with cells were and activities were As shown in treatment increased by when cells were with and of the by was the was in the of an CBP, block of by the activity of was to of that by These data are with the data described with and suggest that competition for CBP is the for the of AR activity by It was shown that CBP can interact with a of transcription factors including and some nuclear receptors (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). the that CBP may physically interact with the pulldown As shown in of CBP were to and were expressed in E. These proteins were and as for interactions with in AR. As shown in whereas binding was with AR was by to the N-terminal of CBP to this interaction was both in the and of and or which the of CBP, not binding to AR that was from These suggest that the region between and of CBP is required for interaction with AR and that this interaction is not ligand binding in vitro. more the interactions between AR and CBP, the pulldown in the AR sequences were to and as the The N-terminal and ligand-binding domains of AR were expressed in E. as proteins and These proteins were and as for interactions with in The in of CBP in in addition to the of to of the of of cell CBP with an this and As shown in whereas binding was with of the were both and These interactions were not of the proteins with not significantly CBP These data suggest that CBP can physically with AR through both the N-terminal and domains in vitro. which in AR is for binding to CBP, of AR These were first in a to transactivation from an that was cells either with AR or its were either or with cells were and activities were As shown in AR in the of The increased the of of by in the of and addition of ligand not significantly this On the other hand, the and not significantly of the as they a DNA-binding These of AR were in the pulldown with as shown in B. As shown in when of the ligand-binding domain or the DNA-binding domain was AR with when in which the of the N-terminal domain of AR is interaction was and a the N terminus in the of CBP-AR interactions. These data suggest that the N-terminal domain of AR is to interact with CBP in with the data in C. In of the ability of CBP to interact with some of the nuclear receptor its role in AR to with glucocorticoid receptor, receptor, receptor, thyroid hormone, retinoic acid, and retinoid X receptors (for a review, see Ref. 26Horwitz K.B. Jackson T.A. Bain D.L. Richer J.K. Takimoto G.S. Tung L. Mol. Endocrinol. 1996; 10: 1167-1177Crossref PubMed Scopus (836) Google Scholar), found that the transcriptional activity of the endogenous AR in LNCaP cells is significantly increased when CBP is this is the first in which CBP or putative coactivator for nuclear receptors has been shown to the activity of an endogenous nuclear receptor than receptors that are ectopically expressed. The of CBP AR function is the result of direct interactions between the proteins as by the data in pulldown assays. either or the as the interactions between AR and CBP and In to the interactions of other nuclear receptors with CBP in which primarily the LBD has been (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar), have found that CBP can to both the NTD and LBD of AR. In of the interactions between the N and of some nuclear receptors (5Ikonen T. Palvimo J.J. Janne O.A. J. Biol. Chem. 1997; 272: 29821-29828Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 6McInerney E.M. Tsai M.J. O’Malley B.W. Katzenellenbogen B.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10069-10073Crossref PubMed Scopus (219) Google Scholar, 7Doesburg P. Kuil C.W. Berrevoets C.A. Steketee K. Faber P.W. Mulder E. Brinkmann A.O. Trapman J. Biochemistry. 1997; 36: 1052-1064Crossref PubMed Scopus (182) Google Scholar), it be to the role of CBP in these interactions for AR. in to the in the of CBP or other putative coactivators with other nuclear receptors, binding not CBP-AR vitro and We not effects under binding not The interaction between AR and CBP is the transcriptional activity of AR is increased in the of when CBP is ectopically expressed are that can for these it is that the have for binding not the in vivo that may be required for may be a protein that is to be which is for ligand-dependent interactions between AR and binding to AR may a in which can in the of CBP, not in the pulldown such that it can act as a be to this CBP may be to AR in the of hormone, binding may be required for the of to be that is for transcriptional by AR. In this it is important to that other putative cofactors for nuclear receptors (e.g. Refs. 19Kamei Y. Xu L. Heinzel T. Torchia J. Kurokawa R. Gloss P. Lin S.-C. Heyman R.A. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 1996; 85: 403-414Abstract Full Text Full Text PDF PubMed Scopus (1928) Google Scholar, 20Chen H. Lin R.J. Schiltz R.L. Chakravarti D. Nash A. Nagy L. Privalsky M.L. Nakatani Y. Evans R.M. Cell. 1997; 90: 569-580Abstract Full Text Full Text PDF PubMed Scopus (1270) Google Scholar, 21Torchia J. Rose D.W. Inostroza J. Kamei Y. Westin S. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 677-684Crossref PubMed Scopus (1108) Google Scholar and S.A. Tsai M.J. O’Malley B.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar) have been shown to interact both with CBP and a of nuclear It has been that a composed of the receptor, CBP, and coactivator may be when the receptor is in a liganded and (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). is to the of such a also to AR. The of in the pulldown that the region of CBP that is required for interaction with AR between and is from the interaction of other nuclear receptors with CBP that have been studied to which have been to the N-terminal Y. Xu L. Heinzel T. Torchia J. Kurokawa R. Gloss P. Lin S.-C. Heyman R.A. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 1996; 85: 403-414Abstract Full Text Full Text PDF PubMed Scopus (1928) Google Scholar, D. T. H. M. Evans R.M. Nature. 1996; PubMed Scopus Google Scholar) (for a review, see Ref. J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). These data suggest that the interaction domain of AR CBP is from the other nuclear receptors studied to the may result from the the system in the studies the pulldown in is required to the for these Conversely, of AR that its N terminus is for binding to to other receptors, AR has a NTD in which a R.L. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). is AR the ability to (5Ikonen T. Palvimo J.J. Janne O.A. J. Biol. Chem. 1997; 272: 29821-29828Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, R.L. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). for the N-terminal CBP interaction the sequences important for transactivation with those required for interactions with CBP in vitro. It be to the activity of is mediated through is to the role of CBP activity of AR and CBP an role between the NTD and LBD of AR. important to AR function is through its interactions with other transcription In this the interaction with AP-1 has been studied AP-1 is an composed of Jun and Fos and its activity is increased by a variety of including P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3279) Google Scholar). a of data from and nuclear receptors, it has been that the cross-talk between nuclear receptors and AP-1 may be of competition for limiting amounts of cofactors in the cell (for a review, see Ref. 10Saatcioglu F. Claret F.X. Karin M. Semin. Cancer Biol. 1994; 5: 347-359PubMed Google Scholar). for this that of CBP and the protein the transcriptional interference with AP-1 by liganded retinoic acid and glucocorticoid receptors Y. Xu L. Heinzel T. Torchia J. Kurokawa R. Gloss P. Lin S.-C. Heyman R.A. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 1996; 85: 403-414Abstract Full Text Full Text PDF PubMed Scopus (1928) Google Scholar). a AP-1 and AR cross-talk that the transcriptional was of direct interactions between AR and AP-1 M. F. P. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). In data that CBP a direct role in this cross-talk and that direct between AR and AP-1 may not be We have also found that the is treatment of LNCaP cells of an these data are with the that transcriptional interference between AP-1 and AR is of competition for a of CBP in the cell for the It is the other hand, that a composed of of and CBP may in the cell Jun and Fos with of CBP than AR and other nuclear receptors (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). is to such are found in the cell. CBP was identified as a CREB binding protein J. P. Claret F.X. T. Karin M. J. M. Nature. 1994; PubMed Scopus Google Scholar, M.R. Nature. 1994; PubMed Scopus Google Scholar) and shown to a of proteins in transcriptional (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). CBP has activity and can with other proteins that also have activities (for reviews, see Refs. R. Biol. Chem. 1996; 377: Google Scholar and J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). It is that of an of that is more to the interaction of the transcriptional with and in of is to the in of the activity that is with CBP for nuclear receptor function and it is required for of AR transactivation CBP may have a role in a of can interact with CBP R. Biol. Chem. 1996; 377: Google Scholar, J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). with one of the CBP have a of with and have been in the CBP in F. J.J. M. D.J. 1995; PubMed Scopus Google C. F. H. M. R.M. A. 1997; PubMed Scopus Google Scholar). the important role of androgens and AR in the and progression of prostate and the role of CBP in AR which is in this it be important to are in the CBP activity of prostate We H. and Palvimo for of also found that CBP AR J. and A. Proc. Natl. Acad. Sci. U. S. A.