Androgens, mainly testosterone and 5alpha-dihydrotestosterone (DHT) play significant role in the growth and development of the male reproductive organs. These steroid hormones bring about their biological functions through their associations with Androgen receptor (AR), a 110 KDa ligand dependent transcription factor that falls under the group of nuclear receptor superfamily (1,2). DHT binds the receptor with high affinity compared to testosterone. The AR gene is located in the X chromosome at Xq11-12 site (3). AR is cytosolic protein, which in the ligand unbound state, is present as a complex with various Heat shock proteins primarily Hsp70, 90 and 56 as well as p23. Upon ligand binding, it dissociates from the complex (4). AR is found to be expressed in a number of tissues and cells including prostate, testis, seminal vescicle, epididymis, skin, skeletal muscle, cardiac muscle, liver and central nervous system (5).

The protein has four functional domains- an N terminal domain (NTD), a DNA binding domain (DBD), a hinge region and a Ligand binding Domain (LBD). The DBD is a 658 amino acid residue region that has Zn finger motifs which allows it bind to DNA (6). The rest of the domains are involved in dimerization and ligand binding. Two phosphorylation events are proposed to play very important role in the activation of the receptor upon ligand binding. The first phosphorylation event releases the ligand binding domain for hormone binding. The subsequent phosphorylation event is triggered upon hormone binding (7).

Activated AR upon ligand binding undergoes conformational change to form a homodimer and interacts tightly with the Androgen Response Element (ARE). The androgen receptor is known to bind to many co-regulators at different time points and in different cell types (8). This DNA protein complex triggers the expression of various target genes that are associated with the male phenotype. Modulation of the AR activity is carried out by several transcription factors like ARA70 (9), TR4 (10), SRC family members (11) and CBP/p300 (12) and other associated proteins. FXXLF and WXXLF motifs containing coactivators such as the p160 members bind with the AF2 region of the Ligand Binding Domain of the AR (13).

Androgen receptors are known to induce apoptosis under certain conditions. Various regulators that regulate androgen induced apoptosis include BRCA1 (14) and Smad3 (15) and Akt (16). Mutation in AR are also known to be associated in a number of diseases including spinal and bulbar muscular atrophy (SBMA) or Kennedy’s disease and Androgen Insensitivity syndrome (AIS)(17,18,19). Abnormal amplification of the androgen gene as well as deregulation of AR gene expression have been shown to be associated with prostate cancer (20).

References

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6. Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT. Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4758-63.

7. Brinkmann AO. Lessons to be learned from the androgen receptor. Eur J Dermatol. 2001 Jul-Aug;11(4):301-3.

8. Heinlein C. A. and Chang C. (2002) Structural and functional analysis of the androgen receptor. In: Androgens and Androgen Receptor, Chang C. (ed.), Kluwer Academic Publishers, Norwell, MA

9. Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5517-21.

10. Lee YF, Lee HJ, Chang C. Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily. J Steroid Biochem Mol Biol. 2002 Aug;81(4-5):291-308.

11. Bevan CL, Hoare S, Claessens F, Heery DM, Parker MG. The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol. 1999 Dec;19(12):8383-92.

12. Frønsdal K, Engedal N, Slagsvold T, Saatcioglu F. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. J Biol Chem. 1998 Nov 27;273(48):31853-9.

13. Gao T, Brantley K, Bolu E, McPhaul MJ. RFG (ARA70, ELE1) interacts with the human androgen receptor in a ligand-dependent fashion, but functions only weakly as a coactivator in cotransfection assays. Mol Endocrinol. 1999 Oct;13(10):1645-56.

14. Yeh S, Hu YC, Rahman M, Lin HK, Hsu CL, Ting HJ, Kang HY, Chang C. Increase of

15. androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11256-61.

16. Kang HY, Lin HK, Hu YC, Yeh S, Huang KE, Chang C. From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3018-23.

17. Lin HK, Yeh S, Kang HY, Chang C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7200-5.

18. Rajender S, Pooja S, Gupta NJ, Chakrabarty B, Singh L, Thangaraj K. G708E Mutation in the Androgen Receptor Results in Complete Loss of Androgen Function. J Androl. 2010 Jul 29.

19. Nagaraja MR, Rastogi A, Raman R, Gupta DK, Singh SK. Mutational analysis of the androgen receptor gene in two Indian families with partial androgen insensitivity syndrome. J Pediatr Endocrinol Metab. 2009 Dec;22(12):1169-73.

20. Finsterer J. Perspectives of Kennedy's disease. J Neurol Sci. 2010 Nov 15;298(1-2):1-10. Epub 2010 Sep 16.

21. Dehm SM, Tindall DJ. Regulation of androgen receptor signaling in prostate cancer. Expert Rev Anticancer Ther. 2005 Feb;5(1):63-74.