Androgen response elements

Upon hormone binding, the AR is translocated from the cytoplasm into the nucleus where it uses its DNA binding domain to interact as a homodimer to specific

DNA sequences termed androgen response elements (AREs). These elements are generally located at the promoter or enhancer regions of AR target genes such as probasin (Rennie etal. 1993), prostate binding protein (PBP) (Claessens etal. 1989; 1993), glandular kallikrein-2 (hKLK2) (Murtha etal. 1993), prostate specific antigen (PSA) (Riegman etal. 1991) and many others (for review see Chang etal. 1995).

The consensus DNA-binding site for the AR is made up of two imperfect palindromic 6-base-pair (bp) elements (inverted repeats) separated by a 3-bp spacer: 5'-GG(A/T)ACAnnnTGTTCT-3' (Roche etal. 1992). Such a binding site can also be recognized by the progesterone, glucocorticoid and mineralocorticoid receptors. Besides this conventional ARE, specific sequences bound by the AR have been identified in a random sequence selection assay and in androgen-regulated genes (Adler etal. 1993; Claessens etal. 1996; Rennie etal. 1993; Rundlett and Miesfeld 1995; Verrijdt etal. 1999; 2002; Zhou etal. 1999). These motifs are partial direct repeats of the canonical 5'-TGTTCT-3' hexamer. AR binds this direct repeat possibly by dimerizing on the DNA in a "head-to-tail" conformation, while the consensus ARE receptor is bound in the dimer conformation "head-to-head" (Verrijdt etal. 2003). Binding to DNA is followed by interaction of the receptor with components of the basal transcription machinery such as TFIIH (Lee et al. 2000), TFIIF (Reid et al. 2002), TBP (McEwan and Gustafsson 1997), sequence specific transcription factors (Ning and Robins 1999), and different cofactor proteins. This leads to up-or downregulation of transcription of the target genes (Quigley etal. 1995; Tsai and O'Malley 1994).

In addition to the activation of gene expression, the AR is known to repress the expression of a number of genes (Leger etal. 1987; Persson etal. 1990) and signaling by ß-catenin/TCF (Chesire and Issac 2002) but the mechanisms used are less well understood. A number of studies have produced the following results to describe negative regulation of gene expression by the AR.

Deletion and protein binding studies have shown that the NH2-terminus of the AR is required for the inhibition of TGF-ß signaling through binding of the AR to Smad3. This inhibits the interaction of Smad3 to Smad-binding element in TGF-ß regulated promoters (Chipuk et al. 2002). NH2-terminal region of the AR has also been reported to bind to Ets-related transcription factors in the inhibition of matrix metalloproteinase gene expression (Schneikert et al. 1996). Furthermore NH2-terminal and COOH-terminal regions of the AR have been shown to form a complex with the pro-apoptotic protein forkhead and rhabdomyosarcoma (FKHR) to block the binding of this factor to its DNA response elements. This suppresses FKHR's transcriptional activity and its ability to regulate Fas ligand expression and to induce apoptosis and cell cycle arrest ofprostate cancer cells (Li etal. 2003). Thus, although a number of data exist on how the AR downregulates gene expression, so far, no one particular region in the receptor has been identified for the repression.

The AR seems to use all its regulatory domains in protein-protein interactions to either inhibit the DNA binding activity or the transactivation function of a number of transcription factors without necessarily binding to DNA.

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