TABLE 4

AR

Receptor nomenclature NR2B1
Receptor code 4.10.1:AG:3:C4
Other names AIS, DHTR, dihydrotestosterone receptor, HUMARA, KD, NR3C4, SBMA, SMAX1, TFM
Molecular information Hs: 919aa, P10275, chr. Xq111,2
Rn: 902aa, P15207, chr. Xq223
Mm: 899aa, P19091, chr. X C346
DNA binding
   Structure Homodimer
   HRE core sequence GGTACANNNTGTTCT (GRE, palindrome)
Partners HSP90 (physical): cellular localization, specify protein stability7,8; HMGB (physical, functional): DNA binding9,10
Agonists Mibolerone (1.65 nM),* DHT (2.23 nM), androstenedione (2.75 nM), methyltrienolone (3.07 nM),* testosterone (15.9 nM)* [IC50]2
Fluoxymesterone
Antagonists Hydroxyflutamide, bicalutamide, nilutamide, mifepristone, cyproterone acetate
Coactivators RNF14, NCOA2, NCOA4, Fhl2, TGFB1I1, RAN1124
Biologically important isoforms AR-A {Hs}:187aa truncated from the N terminus2528; AR-B {Hs}: 110 kDa2528
Tissue distribution Bone marrow, mammary gland, muscle, prostate, stem cells, testes, preputial gland, scrotal skin, vagina {Rn} [Western blot]29
Functional assay Treatment of castrated rats with AR ligands possessing anabolic activity results in increased skeletal muscle mass {Rn}30; androgen treatment causes increased expression of sex hormone-binding globulin in the hepatocarcinoma cell line HepG2 {Hs}31; treatment of castrated rats with AR ligands possessing anabolic activity results in increased weight of prostate and seminal vesicles {Rn}30
Main target genes Activated: PSA {Hs, Rn, Mm},32,33 probasin {Rn},34 Slp {Mm},35 prostatein C3 {Rn},36 SC {Hs}37,38
Mutant phenotype Male mice lacking AR–/– exhibit insulin resistance and impaired glucose tolerance {Mm} [knockout]3941; male mice lacking AR in Sertoli cells exhibit infertility with defective spermatogenesis and hypotestosteronemia {Mm} [knockout]42
Human disease Prostate cancer: mutations of AR affecting ligand binding as well as gene amplification of AR have been described43; androgen insensitivity syndrome: mutations of AR affecting ligand binding, DNA binding or nuclear localization44,45; Kennedy's disease (poly-Q): spinobulbar muscular atrophy is an X-linked form of motor neuron disease characterized by progressive atrophy of the muscles, dysphagia, dysarthria, and mild androgen insensitivity caused by CAG repeat expansion in the AR gene4648; Klinefelter's syndrome (47, XXY, hypogonadism): characterized by undeveloped testes and sterility, skewed inactivation of the X-chromosome seems to contribute to reduced AR expression49,50
  • aa, amino acids; chr., chromosome; HRE, hormone response element; DHT, dihydrotestosterone; GRE, glucocorticoid response element

  • * Radioligand

  • 1. Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, and Willard HF (1989) Androgen receptor locus on the human X chromosome: regional localization to Xq11–12 and description of a DNA polymorphism. Am J Hum Genet 44: 264-269

  • 2. Fang H, Tong W, Branham WS, Moland CL, Dial SL, Hong H, Xie Q, Perkins R, Owens W, and Sheehan DM (2003) Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem Res Toxicol 16: 1338-1358

  • 3. Tan JA, Joseph DR, Quarmby VE, Lubahn DB, Sar M, French FS, and Wilson EM (1988) The rat androgen receptor: primary structure, autoregulation of its messenger ribonucleic acid, and immunocytochemical localization of the receptor protein. Mol Endocrinol 2: 1276-1285

  • 4. Eicher EM, Nesbitt MN, and Francke U (1972) Cytological identification of the chromosomes involved in Searle's translocation and the location of the centromere in the X chromosome of the mouse. Genetics 71: 643-648

  • 5. Francke, U. and Taggart, R.T. (1980) Comparative gene mapping: order of loci on the X chromosome is different in mice and humans. Proc Natl Acad Sci USA 77: 3595-3599

  • 6. Lyon MF and Hawkes SG (1970) X-linked gene for testicular feminization in the mouse. Nature (Lond) 227: 1217-1219

  • 7. Georget V, Terouanne B, Nicolas JC, and Sultan C (2002) Mechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor. Biochemistry 41: 11824-11831

  • 8. Marivoet S, Dijck PV, Verhoeven G, and Heyns W (1992) Interaction of the 90-kDa heat shock protein with native and in vitro translated androgen receptor and receptor fragments. Mol Cell Endocrinol 88: 165-174

  • 9. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, and Edwards DP (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol 18: 4471-4487

  • 10. Verrijdt G, Haelens A, Schoenmakers E, Rombauts W, and Claessens F (2002) Comparative analysis of the influence of the high-mobility group box 1 protein on DNA binding and transcriptional activation by the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. Biochem J 361: 97-103

  • 11. Chan KK, Tsui SK, Ngai SM, Lee SM, Kotaka M, Waye MM, Lee CY, and Fung KP (2000) Protein-protein interaction of FHL2, a LIM domain protein preferentially expressed in human heart, with hCDC47. J Cell Biochem 76: 499-508

  • 12. Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A, and Chang C (1999) Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem 274: 8316-8321

  • 13. Geserick C, Meyer HA, Barbulescu K, and Haendler B (2003) Differential modulation of androgen receptor action by deoxyribonucleic acid response elements. Mol Endocrinol 17: 1738-1750

  • 14. Hsiao PW, Lin DL, Nakao R, and Chang C (1999) The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 274: 20229-20234

  • 15. Hu YC, Yeh S, Yeh SD, Sampson ER, Huang J, Li P, Hsu CL, Ting HJ, Lin HK, Wang L, et al. (2004) Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. J Biol Chem 279: 33438-33446

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

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

  • 18. Kang Z, Pirskanen A, Janne OA, and Palvimo JJ (2002) Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J Biol Chem 277: 48366-48371

  • 19. Mestayer C, Blanchere M, Jaubert F, Dufour B, and Mowszowicz I (2003) Expression of androgen receptor coactivators in normal and cancer prostate tissues and cultured cell lines. Prostate 56: 192-200

  • 20. Miyamoto H, Rahman M, Takatera H, Kang HY, Yeh S, Chang HC, Nishimura K, Fujimoto N, and Chang C (2002) A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth. J Biol Chem 277: 4609-4617

  • 21. Miyoshi Y, Ishiguro H, Uemura H, Fujinami K, Miyamoto H, Miyoshi Y, Kitamura H, and Kubota Y (2003) Expression of AR associated protein 55 (ARA55) and androgen receptor in prostate cancer. Prostate 56: 280-286

  • 22. Muller JM, Isele U, Metzger E, Rempel A, Moser M, Pscherer A, Breyer T, Holubarsch C, Buettner R, and Schule R (2000) FHL2, a novel tissue-specific coactivator of the androgen receptor. EMBO (Eur Mol Biol Organ) J 19: 359-369

  • 23. Ye X, Han SJ, Tsai SY, DeMayo FJ, Xu J, Tsai MJ, and O'Malley BW (2005) Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice. Proc Natl Acad Sci USA 102: 9487-9492

  • 24. Yeh S, Sampson ER, Lee DK, Kim E, Hsu CL, Chen YL, Chang HC, Altuwaijri S, Huang KE, and Chang C (2000) Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer. J Formos Med Assoc 99: 885-894

  • 25. Gao T and McPhaul MJ (1998) Functional activities of the A and B forms of the human androgen receptor in response to androgen receptor agonists and antagonists. Mol Endocrinol 12: 654-663

  • 26. Liegibel UM, Sommer U, Boercsoek I, Hilscher U, Bierhaus A, Schweikert HU, Nawroth P, and Kasperk C (2003) Androgen receptor isoforms AR-A and AR-B display functional differences in cultured human bone cells and genital skin fibroblasts. Steroids 68: 1179-1187

  • 27. Wilson CM and McPhaul MJ (1994) A and B isoforms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci USA 91: 1234-1238

  • 28. Wilson CM and McPhaul MJ (1996) A and B isoforms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol 120: 51-57

  • 29. Bentvelsen FM, McPhaul MJ, Wilson CM, Wilson JD, and George FW (1996) Regulation of immunoreactive androgen receptor in the adrenal gland of the adult rat. Endocrinology 137: 2659-2663

  • 30. Yin D, Gao W, Kearbey JD, Xu H, Chung K, Marhefka CA, Veverka KA, Miller DD, and Dalton JT (2003) Pharmacodynamics of selective androgen receptor modulators. J Pharmacol Exp Ther 304: 1334-1340

  • 31. Lee IR, Dawson SA, Wetherall JD, and Hahnel R (1987) Sex hormone-binding globulin secretion by human hepatocarcinoma cells is increased by both estrogens and androgens. J Clin Endocrinol Metab 64: 825-831

  • 32. Cleutjens KB, Eekelen CCV, Korput HAVD, Brinkmann AO, and Trapman J (1996) Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 271: 6379-6388

  • 33. Zhang S, Murtha PE, and Young CY (1997) Defining a functional androgen responsive element in the 5′ far upstream flanking region of the prostate-specific antigen gene. Biochem Biophys Res Commun 231: 784-788

  • 34. Rennie PS, Bruchovsky N, Leco KJ, Sheppard PC, McQueen SA, Cheng H, Snoek R, Hamel A, Bock ME, and MacDonald BS (1993) Characterization of two cis-acting DNA elements involved in the androgen regulation of the probasin gene. Mol Endocrinol 7: 23-36

  • 35. Scheller A, Scheinman RI, Thompson E, Scarlett, CO, and Robins DM (1996) Contextual dependence of steroid receptor function on an androgen-responsive enhancer. Mol Cell Endocrinol 121: 75-86

  • 36. Tan JA, Marschke KB, Ho KC, Perry ST, Wilson EM, and French FS (1992) Response elements of the androgen-regulated C3 gene. J Biol Chem 267: 4456-4466

  • 37. Haelens A, Verrijdt G, Callewaert L, Peeters B, Rombauts W, and Claessens F (2001) Androgen-receptor-specific DNA binding to an element in the first exon of the human secretory component gene. Biochem J 353: 611-620

  • 38. Verrijdt G, Schoenmakers E, Alen P, Haelens A, Peeters B, Rombauts W, and Claessens F (1999) Androgen specificity of a response unit upstream of the human secretory component gene is mediated by differential receptor binding to an essential androgen response element. Mol Endocrinol 13: 558-1570

  • 39. Fan W, Yanase T, Nomura M, Okabe T, Goto K, Sato T, Kawano H, Nato S, and Nawata H (2005) Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes 54: 1000-1008

  • 40. Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, and Chang C (2005) Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes 54: 1717-1725

  • 41. Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, and Kato S (2003) Late onset of obesity in male androgen receptor -deficient (AR KO) mice. Biochem Biophys Res Commun 300: 167-171

  • 42. Chang C, Chen YT, Yeh, SD, Xu Q, Wang RS, Guillou F, Lardy H, and Yeh S (2004) Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci USA 101: 6876-6881

  • 43. Linja MJ and Visakorpi T (2004) Alterations of androgen receptor in prostate cancer. J Steroid Biochem Mol Biol 92: 255-264

  • 44. Choong CS, Sturm MJ, Strophair JA, McCulloch RK, and Hurley DM. (1997) Reduced expression and normal nucleotide sequence of androgen receptor gene coding and promoter regions in a family with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf) 46: 281-288

  • 45. Kawate H, Wu Y, Ohnaka K, Tao RH, Nakamura KI, Okabe T, Yanase T, Nawata H, and Takayanagi R (2005) Impaired nuclear translocation, nuclear matrix targeting and intranuclear mobility of mutant androgen receptors carrying amino acid substitutions in the DNA-binding domain derived from androgen insensitivity syndrome patients. J Clin Endocrinol Metab 90: 6162-6169

  • 46. MacLean HE, Choi WT, Rekaris G, Warne GL, and Zajac JD (1995) Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy). J Clin Endocrinol Metab 80: 508-516

  • 47. Neuschmid-Kaspar F, Gast A, Peterziel H, Schneikert J, Muigg A, Ransmayr G, Klocker H, Bartsch G, and Cato AC (1996) CAG-repeat expansion in androgen receptor in Kennedy's disease is not a loss of function mutation. Mol Cell Endocrinol 117: 149-156

  • 48. Sulek A, Hoffman-Zacharska D, Krysa W, Szirkowiec W, Fidzianska E, and Zaremba J (2005) CAG repeat polymorphism in the androgen receptor (AR) gene of SBMA patients and a control group. J Appl Genet 46: 237-239

  • 49. Iitsuka Y, Bock A, Nguyen DD, Samango-Sprouse CA, Simpson JL, and Bischoff FZ (2001) Evidence of skewed X-chromosome inactivation in 47,XXY and 48,XXYY Klinefelter patients. Am J Med Genet 98: 25-31

  • 50. Kotula-Balak M, Bablok L, Fracki S, Jankowska A, and Bilinska B (2004) Immunoexpression of androgen receptors and aromatase in testes of patient with Klinefelter's syndrome. Folia Histochem Cytobiol 42: 215-220