A Direct β-Catenin-independent Interaction between Androgen Receptor and T Cell Factor 4

T cell factor (Tcf) proteins bind β-catenin and are downstream effectors of Wnt/β-catenin signals. A recently demonstrated interaction between β-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/β-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4. Tcf4 bound specifically to a glutathione S-transferase-ARDBD fusion protein and could be coimmunoprecipitated with β-catenin and transfected AR or endogenous AR in prostate cancer cells. Transfected Tcf4 repressed the transcriptional activity of full-length AR and a VP16-ARDBD fusion protein, and this repression was only partially reversed by transfected β-catenin. AR activation by cyproterone acetate, a partial agonist that did not support β-catenin binding to the AR, was also repressed by Tcf4, further indicating that repression was not due to β-catenin sequestration. Tcf4 could recruit β-catenin to the AR DBD in vitro and to the cyproterone acetate-liganded AR in vivo. Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter. These findings indicate that AR and Tcf4 can interact directly and that this interaction may occur on the promoters or enhancers of particular genes. The direct AR-Tcf4 interaction, in conjunction AR- and Tcf4-β-catenin binding, provides a mechanism for cooperative and selective gene regulation by AR and the Wnt/β-catenin-Tcf pathway that may contribute to normal and neoplastic prostate growth. T cell factor (Tcf) proteins bind β-catenin and are downstream effectors of Wnt/β-catenin signals. A recently demonstrated interaction between β-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/β-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4. Tcf4 bound specifically to a glutathione S-transferase-ARDBD fusion protein and could be coimmunoprecipitated with β-catenin and transfected AR or endogenous AR in prostate cancer cells. Transfected Tcf4 repressed the transcriptional activity of full-length AR and a VP16-ARDBD fusion protein, and this repression was only partially reversed by transfected β-catenin. AR activation by cyproterone acetate, a partial agonist that did not support β-catenin binding to the AR, was also repressed by Tcf4, further indicating that repression was not due to β-catenin sequestration. Tcf4 could recruit β-catenin to the AR DBD in vitro and to the cyproterone acetate-liganded AR in vivo. Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter. These findings indicate that AR and Tcf4 can interact directly and that this interaction may occur on the promoters or enhancers of particular genes. The direct AR-Tcf4 interaction, in conjunction AR- and Tcf4-β-catenin binding, provides a mechanism for cooperative and selective gene regulation by AR and the Wnt/β-catenin-Tcf pathway that may contribute to normal and neoplastic prostate growth. The androgen receptor (AR) 1The abbreviations used are: AR, androgen receptor; DBD, DNA binding domain; LBD, ligand binding domain; ARE, androgen-responsive element; HMG, high mobility group; Tcf4, T cell factor 4; TLE, transducin-like enhancers of split; ER, estrogen receptor; GST, glutathione S-transferase; DHT, dihydrotestosterone; CPA, cyproterone acetate; CS-FCS, charcoal-dextran-stripped fetal calf serum; NRS, nonimmune rabbit serum; ERE, estrogen-responsive element; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; CMV, cytomegalovirus. is a steroid hormone receptor member of the larger nuclear receptor superfamily and plays a central role in normal male development and prostate cancer (1Quigley C.A. De Bellis A. Marschke K.B. el Awady M.K. Wilson E.M. French F.S. Endocr. Rev. 1995; 16: 271-321Crossref PubMed Google Scholar, 2Brinkmann A.O. Blok L.J. de Ruiter P.E. Doesburg P. Steketee K. Berrevoets C.A. Trapman J. J. Steroid Biochem. Mol. Biol. 1999; 69: 307-313Crossref PubMed Scopus (257) Google Scholar). It contains a highly conserved central DNA binding domain (DBD), a C-terminal ligand binding domain (LBD), and a large N-terminal transactivation domain. AR activation by androgen binding causes a conformational change that enhances nuclear localization, homodimerization, and binding to specific sequences (androgen-responsive elements, AREs) located in androgen-regulated genes. The androgen-induced conformational change in the AR LBD also generates a binding site for a short hydrophobic motif (Leu-X-X-Leu-Leu or LXXLL) found in many transcriptional coactivator proteins, although the AR N terminus contains an LXXLL-like sequence that binds strongly to the liganded LBD and may compete for binding with other LXXLL-containing coactivators (3He B. Kemppainen J.A. Wilson E.M. J. Biol. Chem. 2000; 275: 22986-22994Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar). Similarly to other steroid hormone and nuclear receptors, protein-protein interactions involving one or more domains of the AR mediate the recruitment of multiple transcription factors, with subsequent chromatin remodeling and transcription of androgen regulated genes (4McKenna N.J. Lanz R.B. O'Malley B.W. Endocr. Rev. 1999; 20: 321-344Crossref PubMed Scopus (1655) Google Scholar). The binding of AR and other steroid hormone receptors to DNA can be enhanced by HMG-1 and HMG-2, related nonsequence-specific DNA binding proteins characterized by a high mobility group (HMG) box DBD (5Onate S.A. Prendergast P. Wagner J.P. Nissen M. Reeves R. Pettijohn D.E. Edwards D.P. Mol. Cell. Biol. 1994; 14: 3376-3391Crossref PubMed Google Scholar, 6Verrier C.S. Roodi N. Yee C.J. Bailey L.R. Jensen R.A. Bustin M. Parl F.F. Mol. Endocrinol. 1997; 11: 1009-1019Crossref PubMed Scopus (71) Google Scholar, 7Romine L.E. Wood J.R. Lamia L.A. Prendergast P. Edwards D.P. Nardulli A.M. Mol. Endocrinol. 1998; 12: 664-674Crossref PubMed Scopus (53) Google Scholar, 8Boonyaratanakornkit V. Melvin V. Prendergast P. Altmann M. Ronfani L. Bianchi M.E. Taraseviciene L. Nordeen S.K. Allegretto E.A. Edwards D.P. Mol. Cell. Biol. 1998; 18: 4471-4487Crossref PubMed Scopus (304) Google Scholar, 9Zhang C.C. Krieg S. Shapiro D.J. Mol. Endocrinol. 1999; 13: 632-643Crossref PubMed Google Scholar, 10Melvin V.S. Edwards D.P. Steroids. 1999; 64: 576-586Crossref PubMed Scopus (71) Google Scholar). HMG box-containing proteins have an architectural function based on the ability of the HMG box to bind to the minor groove of the DNA helix and induce a sharp bend. This change in local DNA structure appears to be the major factor responsible for HMG-1 and -2 stabilization of steroid hormone receptor binding to DNA, although weak protein-protein interactions may also play a role. We recently demonstrated an interaction between the AR and the sequence-specific HMG box transcription factor SRY, the Y-chromosome encoded protein required for male sex determination and founding member of the SOX family of HMG proteins (11Yuan X. Lu M.L. Li T. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The interaction was direct and by the AR DBD and the HMG domain of on this have the AR can interact directly with other HMG This study demonstrates an interaction between the AR and T cell factor a member of the cell family that is in multiple and prostate V. N. P. 1998; PubMed Scopus Google Scholar, N. V. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. R. 2000; Google Scholar, J. de PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. J. PubMed Scopus Google Scholar). Tcf4 and the other proteins and are sequence-specific HMG box transcription that function the downstream effectors of Wnt/β-catenin A. J. PubMed Scopus Google Scholar, K. J. R. Cell. 69: Full Text PDF PubMed Scopus Google Scholar, J. J.P. M. L. R. PubMed Scopus Google Scholar, M. de M. J. S. V. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. M. R. PubMed Scopus Google Scholar, V. N. de R. B. 1997; 275: PubMed Scopus Google Scholar, V. N. B. 1997; 275: PubMed Scopus Google Scholar, de R. M. J. J. A. T. A. M. M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, L. K. 1997; PubMed Scopus Google Scholar). the of nuclear the proteins strongly transcription binding of the family of transcriptional transducin-like enhancers of J. de PubMed Scopus Google Scholar, S. N.J. S. PubMed Scopus Google Scholar, J. M. J. J. P. de 1998; PubMed Scopus Google Scholar, R.A. J. M. A. 1998; PubMed Scopus Google Scholar, S. S. A. 1998; PubMed Scopus Google Scholar). is by a conserved N-terminal in the proteins and a between the N-terminal β-catenin binding site and HMG box in the of β-catenin by or other in nuclear and binding, by in the N terminus and β-catenin B. S. P. PubMed Scopus Google Scholar, Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. R.A. Biol. PubMed Scopus Google Scholar). to transcriptional activity by multiple coactivator proteins and de R. M. J. J. A. T. A. M. M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. 1999; PubMed Scopus Google Scholar, A. K. R. J. 2000; PubMed Google Scholar, M. R. M. N. A. S. T. A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. 2000; PubMed Scopus Google Scholar, N. A. A. M. J. 20: PubMed Scopus Google Scholar, Li R.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). stabilization of β-catenin a of has in many with β-catenin due to a of cancer V. N. de R. B. 1997; 275: PubMed Scopus Google Scholar, V. N. B. 1997; 275: PubMed Scopus Google Scholar). have that β-catenin can bind to the AR LBD and function an AR coactivator protein PubMed Scopus Google Scholar, S. 2000; Google Scholar, Li X. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. K. C.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. M. Wilson E.M. M.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). interactions have also between β-catenin and and receptors V. M. S. Biol. 1999; Full Text Full Text PDF PubMed Google Scholar, J. J. M. A. de M. A. J. Biol. PubMed Scopus Google Scholar). These findings have suggested that AR and other nuclear receptors may be Tcf-independent effectors of Wnt/β-catenin and may activity by for nuclear β-catenin. This study demonstrates a direct interaction between Tcf4 and the AR by the AR DBD, indicating a role for Tcf4 in Wnt/β-catenin the A cooperative binding interaction between AR and Tcf4 on the of particular genes is a mechanism by Wnt/β-catenin may of a of genes male development and in prostate and AR was A. A.O. P. J.A. J. Steroid Biochem. PubMed Scopus Google Scholar). in the and the genes and in the (11Yuan X. Lu M.L. Li T. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). estrogen receptor and estrogen-responsive element M. A Tcf4 was S. V. N. de R. B. 1997; 275: PubMed Scopus Google and β-catenin was and and by a of AR in The fusion proteins specific for Tcf4 and and and used in for an N-terminal or The was and in and cells in in with to DNA and of in a of of for with of with steroid and to the was with of CS-FCS, with or the cells with PBS, with of and for a The by the to and the the and of or fusion proteins and proteins by in vitro or in of binding and for in binding in PBS, with and on or cells in to transfected with of AR and Tcf4 DNA in of was with of in of and the of was to cells in of with the was with or with cells with PBS, of immunoprecipitation and and and was by for for of normal rabbit that was to of protein with of protein and of or normal rabbit of and for The in immunoprecipitation in PBS, in and on LNCaP cells the in with and The prostate cancer cell by of J. D.J. M. A. 1997; PubMed Scopus Google was in modified Dulbecco's with and the or in an and to and by with the by or rabbit and Chromatin LNCaP cells for in and in CS-FCS, by with with and for with in chromatin and S. Lu M.L. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and with of rabbit or The for DNA and of the for S. Lu M.L. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Tcf4 binding element in the c-myc the L. B. 1998; PubMed Scopus Google and the major gene and and in the gene S. Lu M.L. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for and of the chromatin used for the AR to Tcf4 a protein-protein interaction between AR and that was by and HMG box DNA binding domains suggested that AR interact directly with other HMG box proteins (11Yuan X. Lu M.L. Li T. Balk S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This was in glutathione fusion protein experiments a fusion protein and HMG proteins that by in vitro HMG protein was T cell factor a member of the family of sequence-specific HMG box proteins that is in multiple prostate PubMed Scopus Google Scholar). Similarly to SRY, Tcf4 bound specifically to a fusion protein the AR DBD, and not to or an AR fusion protein, It be that the in vitro Tcf4 with the with the of the The also bound to the protein, may be a or did not bind to with that β-catenin binds to the AR LBD S. 2000; Google Scholar, Li X. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. K. C.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. M. Wilson E.M. M.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google This that the Tcf4 binding was direct and not by β-catenin. protein, to bind of the experiments there was a interaction between AR and Tcf4 in vivo. cells not endogenous transfected with AR and Tcf4 and for with or androgen and with an or of the showed a and a the of The major was by and was not found in the cells not A larger Tcf4 of has also found in prostate cancer cell and may be due to of has for PubMed Scopus Google Scholar, S. L. A. R. PubMed Scopus Google Scholar). Tcf4 by the in the AR- and cells with Tcf4 was found in the nonimmune or in the cells that transfected only with Tcf4. The Tcf4 was also in the of DHT, further indicating that was by the It be that this not a androgen for Tcf4 binding may stabilization of AR-Tcf4 binding by β-catenin Tcf4 AR in with AR, Tcf4, and an gene to there interactions between AR and Tcf4. cells with an AR and an gene showed transcriptional activity with a Tcf4 in a and in activity the repression was the of Tcf4 of a The repression was activity of a gene regulated by a was not of the used for the further that was of Tcf4 was not due to AR These findings with that also found Tcf4 of AR in PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). genes to the Tcf4 repression was Tcf4 repressed AR transcriptional activity on a gene regulated by an of the with multiple Tcf4 repressed AR activity on an of the by Tcf4 was also in cell cells not These that repression was not or cell A that Tcf4 could interact directly with and transcriptional activity M. R. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of Tcf4 on AR and transcriptional activity to the with AR, Tcf4 did not in transfected cells The was also by with β-catenin that could AR with a that was not by β-catenin and Li X. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These further that the repression of AR by Tcf4 was not a on transcription and suggested that or may Tcf4 interactions with AR Tcf4 of AR of by β-catenin can AR transcriptional activity an interaction with the AR LBD PubMed Scopus Google Scholar, S. 2000; Google Scholar, Li X. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. K. C.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. M. Wilson E.M. M.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). was that Tcf4 repression of AR transcriptional activity of a direct AR-Tcf4 with this of β-catenin could AR transcriptional activity in the of Tcf4 the repression of AR activity was only partially reversed by with of β-catenin that could AR activity in the of transfected Tcf4 A and This suggested that repression of AR activity was not due to of β-catenin. that the repression by Tcf4 a direct interaction with the AR DBD and was not due to on the AR DBD was this the AR DBD was to the transactivation the AR N terminus and The fusion protein could strongly the with of the AR LBD, this activity was Similarly to full-length AR, could be strongly repressed by Tcf4 This that Tcf4 repression of AR transcriptional activity was not due to an on binding and the that was by an interaction with the AR Tcf4 of the AR in the of by the that Tcf4 could bind to the AR DBD and a VP16-ARDBD fusion protein, direct on full-length AR a further to of Tcf4 that of the interaction was to an AR partial agonist that did not support the was cyproterone a used an AR for the of prostate cancer that can AR transcriptional activity in cells transfected with AR and an was in the AR in the of transfected β-catenin A and in to the AR that was strongly by β-catenin the AR was not and was repressed by β-catenin This repression may of coactivator proteins or A study found that β-catenin did not the AR R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). on was used to of Tcf4 on the full-length Similarly to the with and the AR was repressed by Tcf4 conjunction with the this that Tcf4 could interact with the AR of the AR interaction with β-catenin. Tcf4 to the site on Tcf4 that binds β-catenin is located the N terminus the HMG domain is located the terminus This suggested that Tcf4 be to bind β-catenin and AR, β-catenin recruitment to the This was in vitro by β-catenin binding to an AR DBD fusion protein, in the or of Tcf4. Tcf4 could bind strongly to the AR DBD, there was direct binding of β-catenin β-catenin binding was β-catenin and Tcf4 with the fusion protein, indicating that Tcf4 could recruit β-catenin to the AR in vitro to Tcf4 could recruit β-catenin to the full-length AR in vivo. β-catenin was to with the AR, was transfected Tcf4 could induce β-catenin binding to the with AR and Tcf4 and for with or with an or and coimmunoprecipitated proteins by Tcf4 and β-catenin in the the cells transfected with AR and Tcf4 and there was specific of Tcf4 or β-catenin the cells. This was not due to of Tcf4, or AR in the in the and cells and and not This that Tcf4 was not to directly mediate β-catenin binding to the AR that was to be by the to AR and Tcf4 the cells that the in binding of Tcf4 to the AR was by β-catenin. a interaction between the AR, Tcf4, and β-catenin could not be by this did not a in a more was used to Tcf4 could recruit β-catenin to the AR of the β-catenin interaction with the AR cells transfected with AR and or Tcf4, and with β-catenin to the transcriptional activity of the AR β-catenin could the AR was with Tcf4 This was with the in vitro and that Tcf4 could mediate recruitment of β-catenin to the AR in vivo. between AR and Tcf4 in LNCaP and prostate cancer cells to endogenous could be cell endogenous AR a ligand binding domain in and Tcf4, with Tcf4 in PubMed Scopus Google Scholar). S. 2000; Google endogenous AR and β-catenin could be coimmunoprecipitated LNCaP cells and be coimmunoprecipitated cells the of β-catenin that could be coimmunoprecipitated with AR was and a specific coimmunoprecipitated Tcf4 was not in the LNCaP cells not Tcf4 could be specifically in cells with the in AR- and cells the was in cells not in the of androgen or in cells. Chromatin to further the of the AR interaction with Tcf4 and to specifically the that AR can with Tcf4 on the promoters of genes. A of genes have and specific sequences Tcf4 binding to the c-myc binding have L. B. 1998; PubMed Scopus Google Scholar). one of the Tcf4 binding in the c-myc used to AR Chromatin was LNCaP by by or to and by a of a with the major in the gene demonstrated of the AR with this the c-myc Tcf4 binding element this element in the with a in the cells. of the DNA with and immunoprecipitation with an rabbit conjunction with the support the that there is a interaction between endogenous AR and Tcf4. The family of sequence-specific proteins have to function transcription the conserved Wnt/β-catenin with β-catenin the not transcriptional coactivator A. J. PubMed Scopus Google Scholar, J. J.P. M. L. R. PubMed Scopus Google Scholar, M. de M. J. S. V. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. M. R. PubMed Scopus Google Scholar, V. N. de R. B. 1997; 275: PubMed Scopus Google Scholar, V. N. B. 1997; 275: PubMed Scopus Google Scholar, de R. M. J. J. A. T. A. M. M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, L. K. 1997; PubMed Scopus Google Scholar). although genes and c-myc have the of genes directly by this pathway in particular and to be L. B. 1998; PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar, de M. de A. M. P. S. M. R. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). that β-catenin could also function a transcriptional coactivator for the AR an interaction with the AR LBD have that AR be a Tcf-independent of the Wnt/β-catenin pathway PubMed Scopus Google Scholar, S. 2000; Google Scholar, Li X. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. K. C.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. M. Wilson E.M. M.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). This study demonstrates that Tcf4, a protein in multiple prostate cancer cell can interact directly with the This that the AR, a Tcf-independent of Wnt/β-catenin may function with Tcf4 to the of particular genes in to Wnt/β-catenin signals. Tcf4 was in vitro and in to directly interact with the AR DBD, of the β-catenin interaction with the AR Tcf4 could recruit β-catenin to the AR in the of an interaction between β-catenin and the AR a interaction between the full-length AR and Tcf4 by was agonist indicating a role for β-catenin in the AR-Tcf4 binding factor that may of the AR-Tcf4 interaction in is DNA binding, in the of genes that binding for AR and Tcf4. is that the AR-Tcf4 interaction is in the of genes that mediate specific binding of AR and Tcf4. This is by the chromatin immunoprecipitation that AR with Tcf4 binding on the c-myc although is not there are AR binding weak in the c-myc gene that contribute to the Tcf4 was found to AR transcriptional activity in with other recently PubMed Scopus Google Scholar, R. S. S. Wilson E.M. Mol. Cell. Biol. PubMed Scopus Google Scholar). This repression was not due to a in β-catenin coactivator was in β-catenin did not have coactivator and was only partially reversed by with β-catenin. proteins have to transcription recruitment of proteins and for recruitment of J. de PubMed Scopus Google Scholar, J. M. J. J. P. de 1998; PubMed Scopus Google Scholar, R.A. J. M. A. 1998; PubMed Scopus Google Scholar, S. S. A. 1998; PubMed Scopus Google Scholar, M. R. 1999; PubMed Google Scholar). a study found that a protein, of could bind conserved domain to the AR N terminus and AR transcriptional activity X. Li P. Mol. Cell. Biol. PubMed Scopus Google Scholar). This that the AR activity of transfected Tcf4 may be due to ability to the binding of proteins to the It be that of by β-catenin has suggested a mechanism that may contribute to transcriptional activation of proteins by although the proteins bind to on and direct for this is A. J. PubMed Scopus Google Scholar). the ability of β-catenin to AR repression by Tcf4 that β-catenin not a due to the of a A further in this study was that β-catenin did not interact with the is a partial agonist of the AR that has used for the of prostate the for ability to prostate cancer has not PubMed Scopus Google Scholar). to the selective estrogen receptor used in cancer function estrogen receptor in can strongly AR transcriptional activity in LNCaP prostate cancer cells. the mechanism of of other AR partial was the that the interaction between the AR N terminus and LBD did not occur with the AR, indicating that the and AR J.A. K. Wilson E.M. Mol. Endocrinol. 1999; 13: PubMed Scopus Google Scholar). The of this study indicate that of β-catenin binding by the AR LBD may be a factor to the ability of to prostate cancer growth. this is a for the development of more selective androgen receptor between and Tcf4 was in a with Tcf4 of activity in cells S. L. A. R. PubMed Scopus Google Scholar). Tcf4 repression of transcriptional activity was not cell the highly conserved of steroid hormone receptor that Tcf4 or other proteins may interact with steroid hormone or nuclear the ability of AR to interact directly with multiple of the Wnt/β-catenin-Tcf pathway and that with this pathway may be a particular of the a study AR repression by Tcf4 the N-terminal β-catenin binding site and the HMG that direct or AR interactions may be by other domains of Tcf4 PubMed Scopus Google Scholar). are to Tcf4 interaction with other steroid hormone receptors and to further the of particular Tcf4 domains in AR for β-catenin or other coactivators or may contribute to between AR and Tcf4, the in this study a direct cooperative binding for the AR-Tcf4 this the direct AR-Tcf4 interaction conjunction with the architectural of the Tcf4 HMG weak sequence-specific AR and Tcf4 DNA binding interactions on the promoters or enhancers of particular genes. The β-catenin binding and a transcriptional in cells and a for activation signals. This is with AR binding to a Tcf4 binding element in the c-myc gene and with cooperative binding interactions between AR and other sequence-specific transcription J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). It also provides a mechanism by Wnt/β-catenin may contribute to prostate development and by the transcription of specific genes and that a of Wnt/β-catenin genes in prostate may be regulated by AR and Tcf4.

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