Coactivators and corepressors

Activation of transcription by AR is regulated by a number of cellular proteins that interact with the receptor. The best characterized are the p160 SRC (steroid receptor co-activator) family members: SRC-1/NCoA-1 (Alen et al. 1999; Bevan et al. 1999), SRC2/GRIP1 (glucocorticoid receptor-interacting protein 1) /TIF2 (transcription intermediary factor 2) (Berrevoets et al. 1998; Kotaja et al. 2002a; Shang etal. 2002), and SRC3/ACTR (activator ofthe thyroid and retinoic receptor) / AIB1 (amplified in breast cancer)/pCIP (p300/CBP/co-integrator-associated pro-tein)/RAC3 (receptor-associated co-activator 3) /TRAM 1(thyroid hormone receptor activator molecule 1) (Anzick et al. 1997; Chen et al. 1997; Li et al. 1997; Torchia etal. 1997), CREB-bindingprotein (CBP/p300) (Smith etal. 1996; Aarnisalo etal. 1998; Fronsdal etal. 1998), and P/CAF (CBP/p300 associated factor) (Reutens et al. 2001). AR recruits p160 proteins, CBP/p300 and P/CAF to the promoter of target genes (Berrevoets etal. 1998; Shang etal. 2002). These proteins possess his-tone acetyltransferase activity and acetylate both histones and steroid receptors, including the AR (Glass and Rosenfeld 2000; Fu etal. 2000; McKenna and O'Malley 2002). Acetylation of histone tails results in relaxation of chromatin packaging and thereby facilitates gene transcription. Acetylation of AR on the other hand has been shown to be essential for the transcription activation function of the receptor (Fu etal. 2000).

Other proteins, reported to modulate transactivation function of AR through ill-defined pathways are ARA70 (Yeh and Chang 1996), androgen receptor trapped clone 27 (ART-27) (Markus et al. 2002), FHL2 (Muller et al. 2000), ARA54 (Kang etal. 1999), Tip60 (Brady etal. 1999), Ubc9 (Poukka etal. 1999), ARIP3 (AR-interacting protein 3) (Kotaja et al. 2002b), cyclin E (Yamamoto et al. 2000), TRAP220, TRAP170 and TRAP100 subunits of the thyroid hormone receptor-associated protein (TRAP)-Mediator complex (Wang etal. 2002), histone methyl-transferase CARM1 and (P-Catenin (Koh etal., 2002; Yang etal., 2002; Truica etal., 2000), the breast cancer susceptibility gene 1 (BRCA1) (Park etal. 2000; Yeh et al. 2000). Some of these factors, for example ARIP3 and ARA54 act synergistically with the p160 family members, most likely as bridging molecules for the AR and proteins possessing HAT activity (Kang et al. 1999; Kotaja et al. 2002b). Nonetheless, for most co-activator proteins, their mechanism of action is not yet clear.

Interaction of the nuclear receptor with co-activators is mediated through the transcriptional activation domains in the receptors. This includes AF1 in the NH2-terminal domain and AF2 in the HBD. Co-activators interact with the AF2

hydrophobic surface in the HBD through conserved amphipathic alpha helical LXXLL motifs, where L is leucine and X is any amino acid (Le Douarin etal. 1996; Heery etal. 1997). However, it was shown that SRC1 mutant with disrupted LXXLL motif, deficient in binding to the HBD of other nuclear receptor, is still capable of potentiating the transactivation by the AR (Bevan etal. 1999), indicating that regulation of the transactivation function of the AR by SRC1 must occur through another domain of the receptor. Recently p160 co-activators SRC1 and TIF2 have been shown to interact directly with the AF1 function in the AR (Berrevoets et al. 1998; Bevan etal. 1999). This interaction is mediated by the t 5 domain in the AF-1 of the AR. AF2, on the other hand, demonstrated a reduced ability to recruit p160 coactivators (He et al. 1999). Thus, in contrast to other nuclear receptors, recruitment of the co-activators by the AR occurs primarily through the N-terminal AF-1 transactivation domain.

In addition to coactivators, other groups of proteins exist that regulate the activity of the AR in a negative way. These include AP-1 (Murtha et al. 1997; Sato et al. 1997), NFkB (Palvimo etal. 1996), TR4 (testicular orphan receptor 4) (Lee etal. 1999), HBO1 (histone acetyl transferase binding to origin recognition complex 1) (Sharma et al. 2000) and AES (amino-terminal enhancer of split), a member of the highly conserved Groucho/TLE family of corepressors (Yu et al. 2001). The molecular mechanisms that underlie the negative regulation of AR action by these proteins have remained mostly elusive.

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