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

Cellular & Molecular Biology Letters volume 11, pages 109–131 (2006)Cite this article

Abstract

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.

Abbreviations

AATF:

apoptosis antagonizing factor

APIS complex:

AAA proteins independent of 20S

ARA54:

AR-associated protein 54

ARA70:

AR-associated protein 70

ARE:

androgen responsive element

ARNIP:

AR N-terminal interacting protein

bFGF:

basic fibroblast growth factor

CARM1:

coactivator-associated arginine methyltransferase 1

CHIP:

C-terminus Hsp70 interacting protein

DBD:

DNA binding domain

E6-AP:

E6-associated protein

GRIP-1:

glucocorticoid receptor interacting protein 1

GSK3β:

glycogen synthase kinase 3β

HDAC1:

histone deacetylase 1

HECT:

homologous to the E6-AP C-terminus

HEK293:

human embryonal kidney cell line

HepG2:

human hepatoma cell line

Hsp90:

heat shock protein 90

IGF-1:

insulin-like growth factor 1

IL-6:

interleukin 6

KLK2:

kallikrein 2

KLKK:

lysine (K), leucine (L)

LBD:

ligand binding domain

LNCaP:

lymph node carcinoma of prostate cell line

MAPK:

mitogen activated protein kinase

Mdm2:

Murine double minute 2

NcoR:

nuclear receptor corepressor

NEDD8:

neural precursor cell-expressed developmentally down-regulated

NLS:

nuclear localisation signal

p/CAF:

p300/CBP-associated factor

p300/CBP:

CREB-binding protein

PC3:

human prostate carcinoma cell line

PEST:

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

PI3K:

phosphoinositide-3 kinase

PIAS1:

protein inhibitor of activated STAT

PKA:

protein kinase A

PKC:

protein kinase C

PR:

progesterone receptor

PRMT1:

protein arginine methyltransferase 1

PROTAC:

proteolysis targeting chimeric molecule

PSA:

prostate specific antigen

PSMA7:

proteasome alpha subunit 7

P-TEFb:

positive transcription elongation factor b

PTEN:

phosphatase and tensin homolog deleted on chromosome 10

RING:

really interesting new gene

RNA Pol II:

RNA polymerase II

SCF ligase:

Skp2/cullin1/F-box

SMRT:

silencing mediator of retinoic acid and thyroid hormone receptor

SNURF:

small nuclear RING finger

SRC1:

steroid receptor coactivator 1

Sugl:

suppressor of Gal

SUMO:

small ubiquitin-like modifier

SWI/SNF:

mating type switching/sucrose non-fermenting

TBL1:

transducin-β-like

TBLR1:

transduction-β-like-related protein

TBP:

TATA binding protein

TFIIB, D, F, H:

general transcription factors

TRAP:

thyroid hormone receptor-associated protein

TSG101:

tumour susceptibility gene 101

UAC:

ubiquitin activating enzyme

UBC:

ubiquitin conjugating enzyme

References

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

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  5. www.nursa.org

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093, Warsaw, Poland

    Tomasz Jaworski

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Jaworski, T. Degradation and beyond: Control of androgen receptor activity by the proteasome system. Cell. Mol. Biol. Lett. 11, 109–131 (2006). https://doi.org/10.2478/s11658-006-0011-9

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  • DOI: https://doi.org/10.2478/s11658-006-0011-9

Key words

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

Cellular & Molecular Biology Letters

ISSN: 1689-1392

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