Structure of the androgen receptor gene and its mRNA

The AR gene consists of 8 exons (Fig. 2.1) (Lubahn etal. 1989); it shares this gene structure with the other steroid receptors which form a subfamily of the nuclear receptors. Besides the steroid receptors this superfamily also includes the retinoid and thyroid hormone receptors, vitamin D receptors, peroxisome proliferator-activated receptors and a number of orphan receptors (Hager 2000; Owen and Zelent 2000; Whitfield et al. 1999). All the members have a unique molecular structure comprising a COOH-terminal ligand-binding domain, a central DNA-binding domain that is built up of two zinc finger motifs, a hinge region, and anNH2- terminal transactivation domain (Fig. 2.1) (Fuller 1991; Glass etal. 1997; Tilley etal. 1989). In the AR gene the large exon 1 (2731 bp, 1616 bp coding) encodes the transactivation domain; the two zinc fingers of the DNA-binding domain are

Fig. 2.1

Androgen receptor gene and protein

The domain structure of the androgen receptor comprises a COOH-terminal ligand-binding domain, a central DNA-binding domain made up of two zinc finger motifs, a hinge region, and an NH2-terminal transactivation domain. The AR protein is 919 amino acids long. Due to two polymorphic regions, a polyglutamine and a polyglycine stretch, respectively, in the NH2-terminal domain, the individual AR protein size varies to some extent. The AR gene is located on the X chromosome close to the centromere in bands 11.2-12 and comprises 8 exons. The large exon 1 (2731 bp, 1616 bp coding) encodes the transactivation domain. The two zinc fingers of the DNA-binding domain are encoded by exons 2 and 3 (153 and 117 bp), respectively. A small part of exon 3 and the first part of exon 4 (288 bp) contain the information for the hinge region that includes a nuclear translocation signal. The rest of exon 4 together with exons 5 to 8 (145, 131, 158, 157 bp) encode the ligand-binding domain. Two major mRNA species with 10 and 7 kb, respectively, are transcribed from the AR gene. They differ in the length of the 3' untranslated region.

encoded by exons 2 and 3 (153 and 117 bp), respectively. A small part of exon 3 and the first part of exon 4 (288 bp) contain the information for the hinge region that includes a nuclear translocation signal. The rest of exon 4 together with exons 5 to 8 (145, 131, 158, 157 bp) encode the ligand-binding domain (Jenster et al. 1992; Simental etal. 1992).

The promoter of the AR gene lacks TATA and CAAT boxes typical for most eucaryotic promoters. The major start site of transcription is 1.1 kb upstream of the initiator ATG triplet and a second transcription initiation site is at +13 (Faber et al. 1991). The promoter is characterized by a short GC-box at -59 to -31 and a homopurine stretch of alternating adenosine and guanosine residues from -117 to -60 (Tilley et al. 1990a; Faber et al. 1993). Within the GC-box is a binding site for the transcription factor Sp1. Using footprint analysis and reporter gene assays, Faber et al. found out that initiation from the second transcription start site is directed by the GC-box, whereas the first initiation site is dependent upon sequences between —5 and +57 (Faber etal. 1991). Upstream of the transcription initiation site between —380 and —530 is a cAMP response element (CRE) that confers cAMP induction of AR transcription (Mizokami etal. 1994). The region + 109 to +129 forms a stem-loop secondary structure and was shown in reporter gene assays to play an essential role in the induction of AR translation (Mizokami and Chang 1994). Androgens induce downregulation of AR mRNA (Quarmby et al. 1990). Since classical androgen-responsive elements were not found in the AR promoter, this regulation seems to be indirect through interaction with other transcription factors or via binding to sequences similar to androgen-response element half sites.

The major AR mRNA species is 10 kb in size. In addition, a less abundant mRNA of approximately 7 kb is present in human prostate and different androgen responsive tissues (Burgess and Handa 1993; Hirai etal. 1994; Lubahn etal. 1988a). In a LNCaP prostate cancer cell line derived from a lymph node metastasis, an extra low abundant mRNA of 4.7 kb has been described (Trapman et al. 1988). In the major mRNA sequence the open reading frame of approximately 2.7 kb is flanked by a 1.1 kb 5' untranslated region and a very large (6.8 kb) 3' untranslated region (Faber etal. 1991). The 3' untranslated region is shortened in the smaller mRNA species. Two poly-adenylation signals are located at the end of the mRNA, 221 bp apart, a ATTAAA and a CATAAAbox (Faber etal. 1991).

The cDNA encodes a protein of 919 amino acids with a molecular weight of 98.999 kD (Lubahn et al. 1988a). Due to two trinucleotid-repeat polymorphisms in the NH2-terminal region the individual size of the human AR can vary to some extent. A polymorphic CAG repeat encodes a polyglutamine stretch and a polymorphic GGC repeat a polyglycine stretch (La Spada etal. 1991; Lumbroso etal. 1997; Chang et al. 2002; Chen et al. 2002). Comparison with the amino acid sequence of previously cloned steroid hormone receptors showed a high degree of sequence conservation with the progesterone, glucocorticoid, and mineralocorticoid receptors with highest homology in the DNA-binding domain and a small region within the hydrophobic ligand-binding domain (Chang etal. 1988b). These AR domains also show the highest evolutionary conservation. In the rat the amino acid sequence of the DNA-binding and hormone binding domains are identical to the human protein with an overall homology of 85% (Lubahn etal. 1988a).

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