Wikipedia

Receptor de andróxenos

O receptor de andróxenos (AR), tamén chamado NR3C4 (receptor nuclear subfamilia 3, grupo C, membro 4), é un tipo de receptor nuclear[5] que é activado no citoplasma pola unión de calquera das hormonas androxénicas, como a testosterona e a dihidrotestosterona[6] e despois trasladado ao núcleo celular. O receptor de andróxenos humano está codificado no xene AR do cromosoma X. O receptor de andróxenos está relacionado estreitamente co receptor de proxesterona, polo que as proxestinas en maiores doses poden bloquear o receptor de andróxenos.[7][8]

Receptor de andróxenos
Estruturas dispoñibles
PDBBuscar ortólogos: PDBe, RCSB
Identificadores
Nomenclatura
Identificadores
externos
LocusCr. X q12
Padrón de expresión de ARNm
Máis información
Ortólogos
Especies
Humano Rato
Entrez
367 11835
Ensembl
Véxase HS Véxase MM
UniProt
P10275 P19091
RefSeq
(ARNm)
NM_001011645 NM_013476
RefSeq
(proteína) NCBI
NP_000035 NP_038504
Localización (UCSC)
Cr. X:
67.54 – 67.73 Mb 		Cr. X:
97.19 – 97.37 Mb
PubMed (Busca)
367


11835
Receptor de andróxenos
Estrutura cristalina do dominio de unión a ligando do receptor de andróxenos humano unido a un péptido NH2-terminal receptor de andróxenos, ar20-30 e r1881
Identificadores
SímboloAndrogen_recep
PfamPF02166
InterProIPR001103
Función normal do receptor de andróxenos. A testosterona (T) entra na célula e, se está presente a 5-alfa-redutase, é convertida en dihidrotestosterona (DHT). O receptor de andróxenos (AR), despois de que se une a el o esteroide, sofre un cambio conformacional e libera proteínas de choque térmico (htps). A fosforilación (P) ocorre antes ou despois da unión do esteroide. O receptor de andróxenos trasládase ao núcleo onde ocorren a dimerización, a unión ao ADN e o recrutamento de coactivadores. Os xenes diana son transcritos a (ARNm) e traducidos a proteínas.[1][2][3][4]

A principal función do receptor de andróxenos é actuar como factor de transcrición que se une ao ADN que regula a expresión xénica;[9] porén, ten ademais outras funcións.[10] Os xenes regulados por andróxenos son cruciais para o desenvolvemento e mantemento do fenotipo sexual masculino.

Función

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Efectos sobre o desenvolvemento

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Nalgúns tipos de células a testosterona interacciona directamente con receptores de andróxenos, mentres que noutras a testosterona é convertida pola 5-alfa-redutase en dihidrotestosterona, un agonista aínda máis potente da activación de andróxenos.[11] A testosterona parece ser a hormona primaria activadora do receptor de andróxenos no conduto de Wolff, mentres que a dihidrotestosterona é a principal hormona androxénica no seo uroxenital, tubérculo uroxenital e folículos pilosos.[12] A testosterona é, por tanto, a principal responsable do desenvolvemento das características sexuais primarias masculinas, mentres que a dihidrotestosterona é responsable das características sexuais secundarias.

Os andróxenos causan a lenta maduración dos ósos, mais a maioría dos efectos de maduración potentes proceden dos estróxenos producidos por aromatización de andróxenos. Os usuarios de esteroides adolescentes poden encontrar que o seu crecemento queda atrasado polo exceso de andróxenos e/ou estróxenos. As persoas con poucas hormonas sexuais poden ser de baixa altura durante a puberdade pero acaban sendo máis altos de adultos como nas síndromes de insensibilidade aos andróxenos ou aos estróxenos.[13]

Os estudos con ratos knockout indican que o receptor de andróxenos é esencial para a fertilidade feminina normal, sendo necesarios para o desenvolvemento e completa funcionalidade dos folículos ováricos e a ovulación, funcionando por medio de mecanismos intraováricos e neuroendócrinos.[14]

Mantemento da integridade esquelética en machos

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Por medio do receptor de andróxenos, os andróxenos desempeñan un papel clave no mantemento da integridade esquelética dos machos. A regulación desta integridade pola sinalización realizada polo receptor de andróxenos pode atribuírse a osteoblastos e osteocitos.[15]

Papel en femias

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O receptor de andróxenos xoga un papel na regulación das funcións sexuais, somáticas e comportamentais das femias. Os datos experimentais obtidos usando ratos femias knockout para o receptor de andróxenos, proporcionan probas de que a promoción do crecemento cardíaco, hipertrofia renal, crecemento óseo cortical e regulación da estrutura ósea trabecular é o resultado de accións dependentes da unión ao ADN do receptor de andróxenos en femias.

Ademais, a importancia de comprender os receptores de andróxenos en femias débese ao seu papel en varios trastornos xenéticos como a síndrome de insensibilidade aos andróxenos. As insensibilidades completa e parcial aos andróxenos son o resultado de mutacións nos xenes que codifican o receptor de andróxenos. Estas mutacións causan a inactivación do receptor de andróxenos debido a que dan resistencia á testosterona circulante, e coñécense máis de 400 mutacións diferentes no receptor de andróxenos.[16]

Mecanismo de acción

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Xenómico

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O mecanismo primario de acción dos receptores de andróxenos é a regulación directa da transcrición xénica. A unión dun andróxeno ao receptor de andróxenos ten como resultado un cambio conformacional no receptor que, á súa vez, causa a disociación das proteínas de choque térmico, o transporte desde o citosol ao núcleo celular e a dimerización. O dímero receptor de andróxenos únese a unha secuencia específica de ADN chamada elemento de resposta a hormonas. Os receptores de andróxenos interaccionan con outras proteínas no núcleo, orixinando unha regulación á alza ou á baixa da transcrición dun xene específico.[17] A regulación á alza ou a activación da transcrición ten como resultado o incremento da síntese de certos ARN mensaxeiros, os cales, á súa vez, son traducidos polos ribosomas para producir proteínas específicas. Un dos xenes diana coñecidos da activación do receptor de andróxenos é o do receptor do factor de crecemento similar á insulina 1 (IGF-1R).[18] Así, os cambios nos niveis de proteínas específicas nas células é un modo como os receptores de andróxenos controlan o comportamento celular.

Unha función do receptor de andróxenos que é independente da unión directa á súa secuencia de ADN diana é facilitada polo recrutamento por medio doutras proteínas de unión ao ADN. Un exemplo é o factor de resposta ao soro, unha proteína que activa varios xenes que causan o crecemento muscular.[19]

O receptor de andróxenos é modifiicado por modificación postraducional por acetilación,[20] que promove directamente a transactivación mediada polo receptor de andróxenos, a apoptose[21] e o crecemento independente do contacto de células de cancro de próstata.[22] A acetilación do receptor de andróxenos é inducida polos andróxenos[23] e determina o recrutamento na cromatina.[24] A acetilación do sitio do receptor de andróxenos é unha diana clave das histona desacetilases dependentes de NAD+ e dependentes de TSA[25] e dos ARNs non codificantes longos.[26]

Non xenómico

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Máis recentemente, os receptores de andróxenos mostraron ter un segundo modo de acción. Como tamén se observou noutros receptores de hormonas esteroides como os receptores de estróxenos, os receptores de andróxenos poden ter accións que son independentes das súas interaccións co ADN.[10][27] Os receptores de andróxenos interaccionan con certas proteínas de transdución de sinais no citoplasma. A unión de andróxenos a receptores de andróxenos citoplasmáticos poden causar rápidos cambios na función celular independentes de cambios na transcrición xénica, como cambios no transporte iónico. A regulación de vías de transdución de sinais polos receptores de andróxenos citoplásmicos pode levar indirectamente a cambios na transcrición de xenes, por exemplo, ao conducir á fosforilación doutros factores de transcrición.

Xenética

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Xene

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Nos humanos o receptor de andróxenos está codificado no xene AR, localizado no cromosoma X na posición Xq11–12.[28][29]

Deficiencias

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Descubríronse polo menos 165 mutacións causantes de doenzas neste xene. [30] A síndrome de insensibilidade aos andróxenos, anteriormente chamada feminización testicular, é causada por unha mutación no xene do receptor de andróxenos do cromosoma X (locus: Xq11–Xq12).[31] O receptor de andróxenos parece afectar a fisioloxía das neuronas e é defectivo na enfermidade de Kennedy.[32][33] Ademais, as mutacións puntuais e os polimorfismos de repetición de trinucleótidos foron ligados a outros varios trastornos.[34]

Repeticións CAG

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O xene AR contén repeticións CAG que afectan á función receptora, de maneira que poucas repeticións orixinan un incremento da sensibilidade do receptor a andróxenos circulantes e un maior númeor de repeticións causan unha diminución da súa sensibilidade. Os estudos realizados mostraron que hai unha variación racial nas repeticións CAG,[35][36] na que, por exemplo, os afroamericanos teñen menos repeticións que os norteamericanos brancos non hispanos.[35] As tendencias raciais nas repeticións CAG correspóndese coa incidencia e mortalidade do cancro de próstatra neses grupos.

Estrutura

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Os dominios estruturais das dúas isoformas (AR-A e AR-B) do receptor de andróxenos humano. As cifras sobre as barras refírense aos residuos de aminoácidos que separan os dominios que empezan polo N-terminal (esquerda) e acaban no C-terminal (dereita). NTD = dominio N-terminal, DBD = dominio de unión ao ADN, LBD = dominio de unión ao ligando, AF = función de activación.

Isoformas

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Identificáronse dúas isoformas do receptor de andróxenos, denominadas A e B:[37]

Dominios

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Igual que outros receptores nucleares, o receptor de andróxenos é de estrutura modular e está composto polos seguintes dominios funcionais designados con letras do A ao F:[39]

  • A/B) – Dominio regulador N-terminal, que contén:[40]
    • a función de activación 1 (AF-1) entre os residuos 101 e 370, necesaria para unha completa actividade transcricional activada por ligando;
    • a función de activación 5 (AF-5) entre os residuos 360–485, que é responsable da actividade constitutiva (actividade que presenta sen ter unido o ligando);
    • a superficie de dimerización, que abrangue os residuos 1–36 (contén o motivo FXXLF; onde F = fenilalanina, L = leucina e X = calquera residuo de aminoácido) e 370–494, ambos os cales interaccionan co dominio de unión ao ligando (LBD) nunha interacción intramolecular[41][42][43] cabeza con cola.[44][45][46]
  • C) – Domino de unión ao ADN (DBD).
  • D) – Rexión bisagra; rexión flexible que conecta o DBD co LBD; xunto co DBD, contén un sinal de localización nuclear dependente de ligando.[47]
  • E) – Dominio de unión ao ligando (LBD), que contén:
  • F) – Dominio C-terminal.

Variantes de empalme

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AR-V7 é unha variante de empalme ou splicing do receptor de andróxenos que se pode detectar en células tumorias circulantes de pacientes de cancro de próstata metastáticos.[49][50] e serve para predicir a resistencia a algúns fármacos.[51]

Importancia clínica

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Unha expresión alta en receptores de andróxenos foi ligada á agresión e libido ao afectar os eixes hipotálamo-hipofisario-adrenal e hipotálamo-hipofisario-gonadal.[52]

A actividade correguladora anormal do receptor de andróxenos pode contribuír á progresión do cancro de próstata.[53]

Ligandos

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Afinidades[a][54]
Composto RBA[b]
Metribolona 100
Dihidrotestosterona 85
Acetato de ciproterona 7,8
Bicalutamida 1,4
Nilutamida 0,9
Hidroxiflutamida 0,57
Flutamida <0,0057
Notas:
  1. ↑ En receptores de andróxenos; medido en tecido prostático humano.
  2. ↑ En relación á Metribolona, que é por definición do 100%

Agonistas

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Mesturados

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Antagonistas

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Como diana de fármacos

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O receptor de andróxenos é unha importante diana terapéutica no cancro de próstata. Así, desenvolvéronse moitos antiandróxenos, que principalmente teñen como diana o dominio de unión ao ligando da proteína.[56] Os ligandos do receptor de andróxenos poden clasificarse segundo a súa estrutura (esteroide ou non esteroide) ou baseándose na súa capacidade para activar ou inhibir a transcrición (agonistas ou antagonistas).[57] Aínda están en proceso de desenvolvemento inhibidores que teñen como diana dominios funcionais alternativos (dominio N-terminal, dominio de unión ao ADN) da proteína.[55]

Interaccións

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O receptor de andróxenos presenta interaccións con:

Notas

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  1. ↑ Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS (xuño de 1995). "Androgen receptor defects: historical, clinical, and molecular perspectives". Endocrine Reviews 16 (3): 271–321. PMID 7671849. doi:10.1210/edrv-16-3-271. 
  2. ↑ Gottlieb B, Lombroso R, Beitel LK, Trifiro MA (xaneiro de 2005). "Molecular pathology of the androgen receptor in male (in)fertility". Reproductive Biomedicine Online 10 (1): 42–8. PMID 15705293. doi:10.1016/S1472-6483(10)60802-4. 
  3. ↑ Choong CS, Wilson EM (decembro de 1998). "Trinucleotide repeats in the human androgen receptor: a molecular basis for disease". Journal of Molecular Endocrinology 21 (3): 235–57. PMID 9845666. doi:10.1677/jme.0.0210235. 
  4. ↑ Meehan KL, Sadar MD (maio de 2003). "Androgens and androgen receptor in prostate and ovarian malignancies". Frontiers in Bioscience 8 (1–3): d780–800. PMID 12700055. doi:10.2741/1063. 
  5. ↑ Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (decembro de 2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacological Reviews 58 (4): 782–97. PMID 17132855. doi:10.1124/pr.58.4.9. 
  6. ↑ Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, Bi BY, Chatterjee B (1999). Regulation of androgen action. Vitamins & Hormones 55. pp. 309–52. ISBN 978-0-12-709855-5. PMID 9949684. doi:10.1016/S0083-6729(08)60938-3. 
  7. ↑ Bardin CW, Brown T, Isomaa VV, Jänne OA (1983). "Progestins can mimic, inhibit and potentiate the actions of androgens". Pharmacology & Therapeutics 23 (3): 443–59. PMID 6371845. doi:10.1016/0163-7258(83)90023-2. 
  8. ↑ Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs 63 (5): 463–92. PMID 12600226. doi:10.2165/00003495-200363050-00003. 
  9. ↑ Mooradian AD, Morley JE, Korenman SG (febreiro de 1987). "Biological actions of androgens". Endocrine Reviews 8 (1): 1–28. PMID 3549275. doi:10.1210/edrv-8-1-1. 
  10. ↑ 10,0 10,1 Heinlein CA, Chang C (outubro de 2002). "The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions". Molecular Endocrinology 16 (10): 2181–7. PMID 12351684. doi:10.1210/me.2002-0070. 
  11. ↑ Davison SL, Bell R (abril de 2006). "Androgen physiology". Seminars in Reproductive Medicine 24 (2): 71–7. PMID 16633980. doi:10.1055/s-2006-939565. 
  12. ↑ Sinisi AA, Pasquali D, Notaro A, Bellastella A (2003). "Sexual differentiation". Journal of Endocrinological Investigation 26 (3 Suppl): 23–28. PMID 12834017. 
  13. ↑ Frank GR (setembro de 2003). "Role of estrogen and androgen in pubertal skeletal physiology". Medical and Pediatric Oncology 41 (3): 217–21. PMID 12868122. doi:10.1002/mpo.10340. 
  14. ↑ Walters KA, Simanainen U, Handelsman DJ (marzo de 2010). "Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models". Human Reproduction Update 16 (5): 543–58. PMID 20231167. doi:10.1093/humupd/dmq003. 
  15. ↑ Sinnesael M, Claessens F, Laurent M, Dubois V, Boonen S, Deboel L, Vanderschueren D (decembro de 2012). "Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from _targeted AR disruption in mouse osteocytes". Journal of Bone and Mineral Research 27 (12): 2535–43. PMID 22836391. doi:10.1002/jbmr.1713. 
  16. ↑ Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A (2008). "Androgen insensitivity syndrome: clinical features and molecular defects". Hormones (Athens). 7 (3): 217–29. doi:10.14310/horm.2002.1201. PMID 18694860 .
  17. ↑ Heemers HV, Tindall DJ (decembro de 2007). "Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex". Endocrine Reviews 28 (7): 778–808. PMID 17940184. doi:10.1210/er.2007-0019. 
  18. ↑ Pandini G, Mineo R, Frasca F, Roberts CT, Marcelli M, Vigneri R, Belfiore A (marzo de 2005). "Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells". Cancer Research 65 (5): 1849–57. PMID 15753383. doi:10.1158/0008-5472.CAN-04-1837. 
  19. ↑ Vlahopoulos S, Zimmer WE, Jenster G, Belaguli NS, Balk SP, Brinkmann AO, Lanz RB, Zoumpourlis VC, Schwartz RJ (marzo de 2005). "Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene". The Journal of Biological Chemistry 280 (9): 7786–92. PMID 15623502. doi:10.1074/jbc.M413992200. 
  20. ↑ Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG (xullo de 2000). "p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation". The Journal of Biological Chemistry 275 (27): 20853–60. PMID 10779504. doi:10.1074/jbc.M000660200. 
  21. ↑ Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, Chang C, Hopp T, Fuqua SA, Jaffray E, Hay RT, Palvimo JJ, Jänne OA, Pestell RG (maio de 2002). "Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function". Molecular and Cellular Biology 22 (10): 3373–88. PMC 133781. PMID 11971970. doi:10.1128/mcb.22.10.3373-3388.2002. 
  22. ↑ Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, Fan S, Rosen E, Palvimo JJ, Jänne OA, Muratoglu S, Avantaggiati ML, Pestell RG (decembro de 2003). "Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth". Molecular and Cellular Biology 23 (23): 8563–75. PMC 262657. PMID 14612401. doi:10.1128/mcb.23.23.8563-8575.2003. 
  23. ↑ Gong J, Zhu J, Goodman OB, Pestell RG, Schlegel PN, Nanus DM, Shen R (marzo de 2006). "Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells". Oncogene 25 (14): 2011–21. PMID 16434977. doi:10.1038/sj.onc.1209231. 
  24. ↑ Fu M, Rao M, Wu K, Wang C, Zhang X, Hessien M, Yeung YG, Gioeli D, Weber MJ, Pestell RG (xullo de 2004). "The androgen receptor acetylation site regulates cAMP and AKT but not ERK-induced activity". The Journal of Biological Chemistry 279 (28): 29436–49. PMID 15123687. doi:10.1074/jbc.M313466200. 
  25. ↑ 25,0 25,1 Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, Powell MJ, Yang T, Gu W, Avantaggiati ML, Pattabiraman N, Pestell TG, Wang F, Quong AA, Wang C, Pestell RG (novembro de 2006). "Hormonal control of androgen receptor function through SIRT1". Molecular and Cellular Biology 26 (21): 8122–35. PMC 1636736. PMID 16923962. doi:10.1128/MCB.00289-06. 
  26. ↑ Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG (agosto de 2013). "lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs". Nature 500 (7464): 598–602. Bibcode:2013Natur.500..598Y. PMC 4034386. PMID 23945587. doi:10.1038/nature12451. 
  27. ↑ Fix C, Jordan C, Cano P, Walker WH (xullo de 2004). "Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells". Proceedings of the National Academy of Sciences of the United States of America 101 (30): 10919–24. Bibcode:2004PNAS..10110919F. PMC 503720. PMID 15263086. doi:10.1073/pnas.0404278101. 
  28. ↑ Chang CS, Kokontis J, Liao ST (abril de 1988). "Molecular cloning of human and rat complementary DNA encoding androgen receptors". Science 240 (4850): 324–6. Bibcode:1988Sci...240..324C. PMID 3353726. doi:10.1126/science.3353726. 
  29. ↑ Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, Geurts van Kessel A, Voorhorst MM, Mulder E, Brinkmann AO (maio de 1988). "Cloning, structure and expression of a cDNA encoding the human androgen receptor". Biochemical and Biophysical Research Communications 153 (1): 241–8. PMID 3377788. doi:10.1016/S0006-291X(88)81214-2. 
  30. ↑ Šimčíková D, Heneberg P (decembro de 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports 9 (1): 18577. Bibcode:2019NatSR...918577S. PMC 6901466. PMID 31819097. doi:10.1038/s41598-019-54976-4. 
  31. ↑ Brown TR (1995). "Human androgen insensitivity syndrome". Journal of Andrology 16 (4): 299–303. PMID 8537246. Arquivado dende o orixinal (abstract) o 2008-07-24. 
  32. ↑ Kennedy WR, Alter M, Sung JH (xullo de 1968). "Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait". Neurology 18 (7): 671–80. PMID 4233749. doi:10.1212/WNL.18.7.671. 
  33. ↑ Yu Z, Dadgar N, Albertelli M, Gruis K, Jordan C, Robins DM, Lieberman AP (outubro de 2006). "Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model". The Journal of Clinical Investigation 116 (10): 2663–72. PMC 1564432. PMID 16981011. doi:10.1172/JCI28773. 
  34. ↑ Rajender S, Singh L, Thangaraj K (marzo de 2007). "Phenotypic heterogeneity of mutations in androgen receptor gene". Asian Journal of Andrology 9 (2): 147–79. PMID 17334586. doi:10.1111/j.1745-7262.2007.00250.x. 
  35. ↑ 35,0 35,1 Sartor O, Zheng Q, Eastham JA (febreiro de 1999). "Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer". Urology 53 (2): 378–80. PMID 9933058. doi:10.1016/s0090-4295(98)00481-6. 
  36. ↑ Weintrob N, Eyal O, Slakman M, Segev Becker A, Israeli G, Kalter-Leibovici O, Ben-Shachar S (2018). "The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities". PLOS ONE 13 (3): e0195046. Bibcode:2018PLoSO..1395046W. PMC 5871002. PMID 29584789. doi:10.1371/journal.pone.0195046. 
  37. ↑ Wilson CM, McPhaul MJ (febreiro de 1994). "A and B forms of the androgen receptor are present in human genital skin fibroblasts". Proceedings of the National Academy of Sciences of the United States of America 91 (4): 1234–8. Bibcode:1994PNAS...91.1234W. PMC 43131. PMID 8108393. doi:10.1073/pnas.91.4.1234. 
  38. ↑ Gregory CW, He B, Wilson EM (decembro de 2001). "The putative androgen receptor-A form results from in vitro proteolysis". Journal of Molecular Endocrinology 27 (3): 309–19. PMID 11719283. doi:10.1677/jme.0.0270309. 
  39. ↑ Brinkmann AO, Klaasen P, Kuiper GG, van der Korput JA, Bolt J, de Boer W, Smit A, Faber PW, van Rooij HC, Geurts van Kessel A (1989). "Structure and function of the androgen receptor". Urological Research 17 (2): 87–93. PMID 2734982. doi:10.1007/BF00262026. 
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