Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

Degradation and beyond: Control of androgen receptor activity by the proteasome system


The androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.



apoptosis antagonizing factor

APIS complex:

AAA proteins independent of 20S


AR-associated protein 54


AR-associated protein 70


androgen responsive element


AR N-terminal interacting protein


basic fibroblast growth factor


coactivator-associated arginine methyltransferase 1


C-terminus Hsp70 interacting protein


DNA binding domain


E6-associated protein


glucocorticoid receptor interacting protein 1


glycogen synthase kinase 3β


histone deacetylase 1


homologous to the E6-AP C-terminus


human embryonal kidney cell line


human hepatoma cell line


heat shock protein 90


insulin-like growth factor 1


interleukin 6


kallikrein 2


lysine (K), leucine (L)


ligand binding domain


lymph node carcinoma of prostate cell line


mitogen activated protein kinase


Murine double minute 2


nuclear receptor corepressor


neural precursor cell-expressed developmentally down-regulated


nuclear localisation signal


p300/CBP-associated factor


CREB-binding protein


human prostate carcinoma cell line


proline (P), glutamic acid (E), serine (S), threonine (T)


phosphoinositide-3 kinase


protein inhibitor of activated STAT


protein kinase A


protein kinase C


progesterone receptor


protein arginine methyltransferase 1


proteolysis targeting chimeric molecule


prostate specific antigen


proteasome alpha subunit 7


positive transcription elongation factor b


phosphatase and tensin homolog deleted on chromosome 10


really interesting new gene


RNA polymerase II

SCF ligase:



silencing mediator of retinoic acid and thyroid hormone receptor


small nuclear RING finger


steroid receptor coactivator 1


suppressor of Gal


small ubiquitin-like modifier


mating type switching/sucrose non-fermenting




transduction-β-like-related protein


TATA binding protein


general transcription factors


thyroid hormone receptor-associated protein


tumour susceptibility gene 101


ubiquitin activating enzyme


ubiquitin conjugating enzyme


  1. 1.

    Wilson, J.D., George, F.W. and Griffin, J.E. The hormonal control of sexual development. Science 211 (1981) 1278–1284.

  2. 2.

    Quigley, C.A., De Bellis, A., Marschke, K.B., El-Awady, M.K., Wilson, E.M. and French, F.S. Androgen receptor defects: historical, clinical and molecular perspectives. Endocr. Rev. 16 (1995) 271–321.

  3. 3.

    Grossmann, M.E., Huang, H. and Tindall, D.J. Androgen receptor signaling in androgen-refractory prostate cancer. J. Natl. Cancer Inst. 93 (2001) 1687–1697.

  4. 4.

    Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R.C., Ghafoor, A., Feuer, E.J. and Thun, M.J. Cancer statistics, 2005. CA Cancer J. Clin. 55 (2005) 10–30.

  5. 5.

  6. 6.

    MacLean, H.E., Warne, G.L. and Zajac J.D. Localization of functional domains in the androgen receptor. J. Steroid Biochem. Mol. Biol. 62 (1997) 233–242.

  7. 7.

    Vanaja, D.K., Mitchell, S.H., Toft, D.O. and Young, C.Y. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 7 (2002) 55–64.

  8. 8.

    Shang, Y., Myers, M. and Brown, M. Formation of androgen receptor transcription complex. Mol. Cell 9 (2002) 601–610.

  9. 9.

    Asirvatham, A.J., Schmidt, M., Gao, B. and Chaudhary, J. Androgens regulate the immune/inflammatory response and cell survival pathways in rat ventral prostate epithelial cells. Endocrinology 147 (2006) 257–271.

  10. 10.

    Burnstein, K.L. Regulation of androgen receptor levels: Implications for prostate cancer progression and therapy. J. Cell. Biochem. 95 (2005) 657–669.

  11. 11.

    Yeap, B.B., Wilce, J.A. and Leedman, P.J. The androgen receptor mRNA. BioEssays 26 (2004) 672–682.

  12. 12.

    Heinlein, C.A. and Chang, C. Androgen receptor (AR) coregulators: an overview. Endocr. Rev. 23 (2002) 175–200.

  13. 13.

    Smith, C.L. and O’Malley, B.W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr. Rev. 25 (2004) 45–71.

  14. 14.

    Sheflin, L., Keegan, B., Zhang, W. and Spaulding, S.W. Inhibiting proteasomes in human HepG2 and LNCaP cells increases endogenous androgen receptor levels. Biochem. Biophys. Res. Commun. 276 (2000) 144–150.

  15. 15.

    Pickart, C.M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70 (2001) 503–533.

  16. 16.

    Thrower, J.S., Hoffman, L., Rechsteiner, M. and Pickart, C.M. Recognition of the polyubiquitin proteolytic signal. EMBO J. 19 (2000) 94–102.

  17. 17.

    Nawaz, Z., Lonard, D.M., Smith, C.L., Lev-Lehman, E., Tsai, S.Y., Tsai, M.J. and O’Malley B.W. The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol. Cell. Biol. 19 (1999) 1182–1189.

  18. 18.

    Smith, C.L., DeVera, D.G., Lamb, D.J., Nawaz, Z., Jiang, Y.H., Beaudet, A.L. and O’Malley, B.W. Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction. Mol. Cell. Biol. 22 (2002) 525–535.

  19. 19.

    Verma, S., Ismail, A., Gao, X., Fu, G., Li, X., O’Malley, B.W. and Nawaz, Z. The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors. Mol. Cell. Biol. 24 (2004) 8716–8726.

  20. 20.

    Beitel, L.K., Elhaji, Y.A., Lumbroso, R., Wing, S.S., Panet-Raymond, V., Gottlieb, B., Pinsky, L. and Trifiro, M.A. Cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity. J. Mol. Endocrinol. 29 (2002) 41–60.

  21. 21.

    Kang, H.Y., Yeh, S., Fujimoto, N. and Chang, C. Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor. J. Biol. Chem. 274 (1999) 8570–8576.

  22. 22.

    Ito, K., Adachi, S., Iwakami, R., Yasuda, H., Muto, Y., Seki, N. and Okano, Y. N-Terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8. Eur. J. Biochem. 268 (2001) 2725–2732.

  23. 23.

    Lin, H.K., Wang, L., Hu, Y.C., Altuwaijri, S. and Chang, C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J. 21 (2002) 4037–4048.

  24. 24.

    Moilanen, A.M., Karvonen, U., Poukka, H., Yan, W., Toppari, J., Jänne, O.A. and Palvimo, J.J. A testis-specific androgen receptor coregulator that belongs to a novel family of nuclear proteins. J. Biol. Chem. 274 (1999) 3700–3704.

  25. 25.

    Poukka, H., Aarnisalo, P., Karvonen, U., Palvimo, J.J. and Jänne, O.A. Ubc9 interacts with the androgen receptor and activates receptor-dependent transcription. J. Biol. Chem. 274 (1999) 19441–19446.

  26. 26.

    Poukka, H., Karvonen, U., Jänne, O.A. and Palvimo, J.J. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc. Natl. Acad. Sci. USA 97 (2000) 14145–14150.

  27. 27.

    Nishida, T. and Yasuda, H. PIAS1 and PIASxα function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription. J. Biol. Chem. 277 (2002) 41311–41317.

  28. 28.

    Moilanen, A.M., Poukka, H., Karvonen, U., Häkli, M., Jänne, O.A. and Palvimo, J.J. Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription. Mol. Cell. Biol. 18 (1998) 5128–3519.

  29. 29.

    Poukka, H., Karvonen, U., Yoshikawa, N., Tanaka, H., Palvimo, J.J. and Jänne, O.A. The RING finger protein SNURF modulates nuclear trafficking of the androgen receptor. J. Cell. Sci. 113 (2000) 2991–3001.

  30. 30.

    Häkli, M., Lorick, K.L., Weissman, A.M., Jänne, O.A. and Palvimo, J.J. Transcriptional coregulator SNURF (RNF4) possesses ubiquitin E3 ligase activity. FEBS Letters 560 (2004) 56–62.

  31. 31.

    Murata, S., Minami, Y., Minami, M., Chiba, T. and Tanaka, K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2 (2001) 1133–1138.

  32. 32.

    Cardozo, C.P., Michaud, C., Ost, M.C., Fliss, A.E., Yang, E., Patterson, C., Hall, S.J. and Caplan, A.J. C-terminal Hsp-interacting protein slows androgen receptor synthesis and reduces its rate of degradation. Arch. Biochem. Biophys. 410 (2003) 134–140.

  33. 33.

    He, B., Bai, S., Hnat, A.T., Kalman, R.I., Minges, J.T., Patterson, C. and Wilson, E.M. An androgen receptor NH2-terminal conserved motif interacts with the COOH terminus of the Hsp70-interacting protein (CHIP). J. Biol. Chem. 279 (2004) 30643–30653.

  34. 34.

    Rechsteiner, M. and Rogers, S.W. PEST sequences and regulation by proteolysis. Trends Biochem. Sci. 21 (1996) 267–271.

  35. 35.

    Wolf, D.H. and Hilt, W. The proteasome: a proteolytic nanomachine of cell regulation and waste disposal. Biochim. Biophys. Acta 1695 (2004) 19–31.

  36. 36.

    Lin, H.K., Hu, Y.C., Lee, D.K. and Chang, C. Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Mol. Endocrinol. 18 (2004) 2409–2423.

  37. 37.

    Yang, L., Wang, L., Lin, H.K., Kan, P.Y., Xie, S., Tsai, M.Y., Wang, P.H., Chen, Y.T. and Chang, C. Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem. Biophys. Res. Commun. 305 (2003) 462–469.

  38. 38.

    Cronauer, M.V., Nessler-Menardi, C., Klocker, H., Maly, K., Hobisch, A., Bartsch, G. and Culig, Z. Androgen receptor protein is down-regulated by basic fibroblast growth factor in prostate cancer cells. Br. J. Cancer 82 (2000) 39–45.

  39. 39.

    Lin, H.K., Yeh, S., Kang, H.Y. and Chang, C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc. Natl. Acad. Sci. USA 98 (2001) 7200–7205.

  40. 40.

    Hu, Y.C., Yeh, S., Yeh, S.D., Sampson, E.R., Huang, J., Li, P., Hsu, C.L., Ting, H.J., Lin, H.K., Wang, L., Kim, E., Ni, J. and Chang, C. Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. J. Biol. Chem. 279 (2004) 33438–33446.

  41. 41.

    Lin, H.K., Hu, Y.C., Yang, L., Altuwaijri, S., Chen, Y.T., Kang, H.Y. and Chang, C. Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J. Biol. Chem. 278 (2003) 50902–50907.

  42. 42.

    Wen, Y., Hu, M.C., Makino, K., Spohn, B., Bartholomeusz, G., Yan, D.H. and Hung, M.C. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 60 (2000) 6841–6845.

  43. 43.

    Salas, T.R., Kim, J., Vakar-Lopez, F., Sabichi, A.L., Troncoso, P., Jenster, G., Kikuchi, A., Chen, S.Y., Shemshedini, L., Suraokar, M., Logothetis, C.J., DiGiovanni, J., Lippman, S.M. and Menter, D.G. Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity. J. Biol. Chem. 279 (2004) 19191–19200.

  44. 44.

    Liao, X., Thrasher, J.B., Holzbeierlein, J., Stanley, S. and Li, B. Glycogen synthase kinase-3beta activity is required for androgen-stimulated gene expression in prostate cancer. Endocrinology 145 (2004) 2941–2949.

  45. 45.

    Gioeli, D., Black, B.E., Gordon, V., Spencer, A., Kesler, C.T., Eblen, S.T., Paschal, B.M. and Weber, M.J. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol. Endocrinol. 20 (2006) 503–515.

  46. 46.

    Fu, M., Wang, C., Zhang, X. and Pestell, R.G. Acetylation of nuclear receptors in cellular growth and apoptosis. Biochem. Pharmacol. 68 (2004) 1199–1208.

  47. 47.

    Ito, A., Kawaguchi, Y., Lai, C.H., Kovacs, J.J., Higashimoto, Y., Appella, E. and Yao, T.P. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 21 (2002) 6236–6245.

  48. 48.

    Cidlowski, J.A. and Cidlowski, N.B. Regulation of glucocorticoid receptors by glucocorticoids in cultured HeLa S3 cells. Endocrinology 109 (1981) 1975–1982.

  49. 49.

    Dace, A., Zhao, L., Park, K.S., Furuno, T., Takamura, N., Nakanishi, M., West, B.L., Hanover, J.A. and Cheng, S. Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. Proc. Natl. Acad. Sci. USA 97 (2000) 8985–8990.

  50. 50.

    Zhu, J., Gianni, M., Kopf, E., Honore, N., Chelbi-Alix, M., Koken, M., Quignon, F., Rochette-Egly, C. and de The, H. Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha) and oncogenic RARalpha fusion proteins. Proc. Natl. Acad. Sci. USA 96 (1999) 14807–14812.

  51. 51.

    Lange, C.A., Shen, T. and Horwitz, K.B. Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc. Natl. Acad. Sci. USA 97 (2000) 1032–1037.

  52. 52.

    Nawaz, Z., Lonard, D.M., Dennis, A.P., Smith, C.L. and O’Malley, B.W. Proteasome-dependent degradation of the human estrogen receptor. Proc. Natl. Acad. Sci. USA 96 (1999) 1858–1862.

  53. 53.

    Gaughan, L., Logan, I.R., Neal, D.E. and Robson, C.N. Regulation of androgen receptor and histone deacatylase 1 by Mdm2-mediated ubiquitylation. Nucleic Acids Res. 33 (2005) 13–26.

  54. 54.

    Tyagi, R.K., Lavrovsky, Y., Ahn, S.C., Song, C.S., Chatterjee, B. and Roy, A.K. Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol. Endocrinol. 14 (2000) 1162–1174.

  55. 55.

    Dai, J.L. and Burnstein, K.L. Two androgen response elements in the androgen receptor coding region are required for cell-specific up-regulation of receptor messenger RNA. Mol. Endocrinol. 10 (1996) 1582–1594.

  56. 56.

    Black, B.E., Vitto, M.J., Gioeli, D., Spencer, A., Afshar, N., Conaway, M.R., Weber, M.J. and Paschal, B.M. Transient, ligand-dependent arrest of the androgen receptor in subnuclear foci alters phosphorylation and coactivator interactions. Mol. Endocrinol. 18 (2004) 834–850.

  57. 57.

    Kinyamu, H.K., Chen, J. and Archer, T.K. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J. Mol. Endocrinol. 34 (2005) 281–297.

  58. 58.

    Kang, Z., Jänne, O.A. and Palvimo, J.J. Coregulator recruitment and histone modifications in transcriptional regulation by the androgen receptor. Mol. Endocrinol. 18 (2004) 2633–2648.

  59. 59.

    Fu, M., Wang, C., Reutens, A.T., Wang, J., Angeletti, R.H., Siconolfi-Baez, L., Ogryzko, V., Avantaggiati, M.L. and Pestell, R.G. p300 and p300/cAMP response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J. Biol. Chem. 275 (2000) 20853–20860.

  60. 60.

    Daujat, S., Bauer, U.M., Shah, V., Turner, B., Berger, S. and Kouzarides, T. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr. Biol. 12 (2002) 2090–2097.

  61. 61.

    Marshall, T.W., Link, K.A., Petre-Draviam, C.E. and Knudsen, K.E. Differential requirement of SWI/SNF for androgen receptor activity. J. Biol. Chem. 278 (2003) 30605–30613.

  62. 62.

    Wang, Q., Sharma, D., Ren, Y. and Fondell, J.D. A coregulatory role for the TRAP-Mediator complex in androgen receptor-mediated gene expression. J. Biol. Chem. 277 (2002) 42852–42858.

  63. 63.

    Huang, Z.Q., Li, J., Sachs, L.M., Cole, P.A. and Wong, J. A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription. EMBO J. 22 (2003) 2146–2155.

  64. 64.

    Lee, D.K. and Chang, C. Molecular communication between androgen receptor and general transcription machinery. J. Steroid Biochem. Mol. Biol. 84 (2003) 41–49.

  65. 65.

    Svejstrup, J.Q. The RNA polymerase II transcription cycle: cycling through chromatin. Biochim. Biophys. Acta 1677 (2004) 64–73.

  66. 66.

    Kang, Z., Pirskanen, A., Jänne, O.A. and Palvimo, J.J. Involvement of proteasome in the dynamic assembley of the androgen receptor transcription complex. J. Biol. Chem. 277 (2002) 48366–48371.

  67. 67.

    Hager, G.L., Nagaich, A.K., Johnson, T.A., Walker, D.A and John, S. Dynamics of nuclear receptor movement and transcription. Biochim. Biophys. Acta 1677 (2004) 46–51.

  68. 68.

    Dennis, A.P. and O’Malley, B.W. Rush hour at the promoter: how the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription. J. Steroid Biochem. Mol. Biol. 93 (2005) 139–151.

  69. 69.

    Lin, H.K., Altuwaijri, S., Lin, W.J., Kan, P.Y., Collins, L.L. and Chang, C. Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells. J. Biol. Chem. 277 (2002) 36570–36576.

  70. 70.

    Makino, Y., Yoshida, T., Yogosawa, S., Tanaka, K., Muramatsu, M. and Tamura, T. Multiple mammalian proteasomal ATPases, but not proteasome itself, are associated with TATA-binding protein and a novel transcriptional activator, TIP 120. Genes Cells 4 (1999) 529–539.

  71. 71.

    Gonzalez, F., Delahodde, A., Kodadek, T. and Johnston, S.A. Recruitment of a 19S proteasome subcomplex to an activated promoter. Science 296 (2002) 548–550.

  72. 72.

    Ferdous, A., Kodadek, T. and Johnston, S.A. A nonproteolytic function of the 19S regulatory subunit of the 26S proteasome is required for efficient activated transcription by human RNA polymerase II. Biochemistry 41 (2002) 12798–12805.

  73. 73.

    vom Baur, E., Zechel, C., Heery, D., Heine, M.J., Garnier, J.M., Vivat, V., Le Douarin, B., Gronemeyer, H., Chambon, P. and Losson, R. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J. 15 (1996) 110–124.

  74. 74.

    Ikezoe, T., Yang, Y., Saito, T., Koeffler, H.P. and Taguchi, H. Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells. Cancer Sci. 95 (2004) 271–275.

  75. 75.

    Sun, L. and Chen, Z.J. The novel functions of ubiquitination in signaling. Curr. Opin. Cell Biol. 16 (2004) 119–126.

  76. 76.

    Salghetti, S.E., Caudy, A.A., Chenoweth, J.G. and Tansey, W.P. Regulation of transcriptional activation domain function by ubiquitin. Science 293 (2001) 1651–1653.

  77. 77.

    Burgdorf, S., Leister, P. and Scheidtmann, K.H. TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination. J. Biol. Chem. 279 (2004) 17524–17534

  78. 78.

    Conaway, R.C., Brower, C.S. and Conaway, J.W. Emerging roles of ubiquitin in transcriptional regulation. Science 296 (2002) 1254–1258.

  79. 79.

    Pham, A.D. and Sauer, F. Ubiquitin-activating/conjugating activity of TAFII250, a mediator of activation of gene expression in Drosophila. Science 289 (2000) 2357–2360.

  80. 80.

    Grossman, S.R., Deato, M.E., Brgnon, C., Chan, H.M., Kung, A.L., Tagami, H., Nakatani, Y. and Livingston, D.M. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300 (2003) 342–344.

  81. 81.

    Ismaili, N., Blind, R. and Garabedian, M.J. Stabilisation of the unliganded glucocorticoid receptor by TSG101. J. Biol. Chem. 280 (2005) 11120–11126.

  82. 82.

    Tanner, T., Claessens, F. and Haelens, A. The hinge region of the androgen receptor plays a role in proteasome-mediated transcriptional activation. Ann. NY Acad. Sci. 1030 (2004) 587–592.

  83. 83.

    Thomas, M., Dadgar, N., Aphale, A., Harrell, J.M., Kunkel, R., Pratt, W.B. and Lieberman, A.P. Androgen receptor acetylation site mutations cause trafficking defects, misfolding and aggregation similar to expanded glutamine tracts. J. Biol. Chem. 279 (2004) 8389–8395.

  84. 84.

    Zhou, Z.X., Kemppainen, J.A. and Wilson, E.M. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol. Endocrinol. 9 (1995) 605–615.

  85. 85.

    Wong, H.Y., Burghoorn, J.A., Van Leeuwen, M., De Ruiter, P.E., Schippers, E., Blok, L.J., Li, K.W., Dekker, H.L., De Jong, L., Trapman, J., Grootegoed, J.A. and Brinkmann, A.O. Phosphorylation of androgen receptor isoforms. Biochem. J. 383 (2004) 267–276.

  86. 86.

    Gioeli, D., Ficarro, S.B., Kwiek, J.J., Aaronson, D., Hancock, M., Catling, A.D., White, F.M., Christian, R.E., Settlage, R.E., Shabanowitz, J., Hunt, D.F. and Weber, M.J. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277 (2002) 29304–29314.

  87. 87.

    Perissi, V., Aggarwal, A., Glass, C.K., Rose, D.W. and Rosenfeld, M.G. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116 (2004) 511–526.

  88. 88.

    Zhang, J., Guenther, M.G., Carthew, R.W. and Lazar, M.A. Proteasomal regulation of nuclear receptor corepressor-mediated repression. Genes Dev. 12 (1998) 1775–1780.

  89. 89.

    Gao, X., Mohsin, S.K., Gatalica, Z., Fu, G., Sharma, P. and Nawaz, Z. Decreased expression of E6-associated protein in breast and prostate carcinomas. Endocrinology 146 (2005) 1707–1712.

  90. 90.

    Jänne, O.A., Moilanen, A.M., Poukka, H., Rouleau, N., Karvonen, U., Kotaja, N., Häkli, M. and Palvimo, J.J. Androgen-receptor-interacting nuclear proteins. Biochem. Soc. Trans. 28 (2000) 401–405.

  91. 91.

    Stenoien, D.L., Cummings, C.J., Adams, H.P., Mancini, M.G., Patel, K., DeMartino, G.N., Marcelli, M., Weigel, N.L. and Mancini, M.A. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8 (1999) 731–741.

  92. 92.

    Fan, M., Bigsby, R.M. and Nephew, K.P. The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERalpha-positive breast cancer cells. Mol. Endocrinol. 17 (2003) 356–365.

  93. 93.

    Abreu-Martin, M.T., Chari, A., Palladino, A.A., Craft, N.A. and Sawyers, C.L. Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol. Cell. Biol. 19 (1999) 5143–5154.

  94. 94.

    Yeh, S., Lin, H.K., Kang, H.Y., Thin, T.H., Lin, M.F. and Chang, C. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc. Natl. Acad. Sci. USA 96 (1999) 5458–5463.

  95. 95.

    Darne, C., Veyssiere, G. and Jean, C. Phorbol ester causes ligand-independent activation of the androgen receptor. Eur. J. Biochem. 256 (1998) 541–549.

  96. 96.

    Nazareth, L.V. and Weigel, N.L. Activation of the human androgen receptor through a protein kinase A signaling pathway. J. Biol. Chem. 271 (1996) 19900–19907.

  97. 97.

    Veldscholte, J., Ris-Stalpers, C., Kuiper, G.G., Jenster, G., Berrevoets, C., Claassen, E., van Rooij, H.C., Trapman, J., Brinkmann, A.O. and Mulder, E. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem. Biophys. Res. Commun. 173 (1990) 534–540.

  98. 98.

    Koivisto, P., Visakorpi, T. and Kallioniemi, O.P. Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand. J. Clin. Lab. Invest. Suppl. 226 (1996) 57–63.

  99. 99.

    Culig, Z., Hobisch, A., Cronauer, M.V., Cato, A.C.B., Hittmair, A., Radmayr, C., Eberle, J., Bartsch, G. and Klocker, H. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol. Endocrinol. 7 (1993) 1541–1550.

  100. 100.

    Veldscholte, J., Voorhorst-Ogink, M.M., Bolt-de Vries, J., van Rooij, H.C., Trapman, J. and Mulder, E. Unusual specificity of the androgen receptor in the human prostate tumor cell line LNCaP: high affinity for progestagenic and estrogenic steroids. Biochim. Biophys. Acta 1052 (1990) 187–194.

  101. 101.

    Cha, T.L., Qiu, L., Chen, C.T., Wen, Y. and Hung, M.C. Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth. Cancer Res. 65 (2005) 2287–2295.

  102. 102.

    Pajonk, F., van Ophoven, A. and McBride, W.H. Hyperthermia-induced proteasome inhibition and loss of androgen receptor expression in human prostate cancer cells. Cancer Res. 65 (2005) 4836–4843.

  103. 103.

    Schneekloth, J.S., Fonseca, F.N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K. and Crews, C.M. Chemical genetic control of protein levels: selective in vivo targeted degradation. J. Am. Chem. Soc. 126 (2004) 3748–3754.

  104. 104.

    Prescott, J. and Coetzee, G.A. Molecular chaperones throughout the life cycle of androgen receptor. Cancer Lett. 231 (2006) 12–19.

  105. 105.

    Vanaja, D.K., Mitchell, S.H., Toft, D.O. and Young, C.Y.F. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 7 (2002) 55–64.

  106. 106.

    Kuduk, S.D., Harris, C.R., Zheng, F.F., Sepp-Lorenzino, L., Ouerfelli, Q., Rosen, N. and Danishefsky, S.J. Synthesis and evaluation of geldanamycin-testosterone hybrids. Bioorg. Med. Chem. Lett. 10 (2000) 1303–1306.

Download references

Author information



Corresponding author

Correspondence to Tomasz Jaworski.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jaworski, T. Degradation and beyond: Control of androgen receptor activity by the proteasome system. Cell. Mol. Biol. Lett. 11, 109 (2006).

Download citation

Key words

  • AR
  • Degradation
  • Prostate cancer
  • Proteasome
  • Transcription
  • Ubiquitin