A Coregulatory Role for the TRAP-Mediator Complex in Androgen Receptor-mediated Gene Expression

University of Maryland, Baltimore, Baltimore, Maryland, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2002; 277(45):42852-8. DOI: 10.1074/jbc.M206061200
Source: PubMed


The human thyroid hormone receptor-associated protein (TRAP)-Mediator complex was originally identified as a large multimeric
complex that copurifies with the thyroid hormone receptor (TR) from HeLa cells and markedly enhances TR-mediated transcription
in vitro. More recent studies have implicated TRAP-Mediator as a coactivator for a broad range of nuclear hormone receptors as well
as other classes of transcriptional activators. Here we present evidence that TRAP-Mediator plays a functional role in androgen
receptor (AR)-mediated transcription. We show that several subunits of the complex ligand-dependently coimmunoprecipitate
with AR from both prostate cancer LNCaP cells and from HeLa cells stably transfected with AR. The 220-kDa subunit of the complex
(TRAP220) can contact the ligand-binding domain of AR in vitro, possibly implicating TRAP220 involvement in targeting AR to the holocomplex. Consistent with a TRAP-Mediator coactivator
role, transient overexpression of the TRAP220, TRAP170, and TRAP100 subunits enhanced ligand-dependent transcription by AR
in cultured cells. Finally, chromatin immunoprecipitation assays show that TRAP220 is recruited to the androgen-responsive
prostate-specific antigen gene promoter in vivo in ligand-stimulated LNCaP cells. Collectively, these data suggest that TRAP-Mediator may play an important coregulatory
role in AR-mediated gene expression.

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    • "The fact that FOXA1 is overexpressed and mutated in hormone-dependent cancers, prostate cancer, and breast cancer, is in concordance with its predominant role in directing AR/ER signaling to drive cancer development.88,89 In addition, knowledge about the multiprotein Mediator complex, which is well-known for its role in bridging enhancer and promoter into close proximity,90 has also contributed to our understanding about chromosome looping involving AR, wherein the silencing of a Mediator subunit MED1 can significantly impair AR transactivation.91 "
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    • "Other coregulatory proteins possessing enzymatic activity have been identified that interact with AR or its associated p160 proteins including CARM1 (methyltransferase), LSD1 (lysine specific demethylase), and CBP/p300 (HAT activity) (Koh et al., 2002; Metzger et al., 2005; Wang et al., 2005). AR can also recruit TRAP220, a subunit of the mediator complex, to target genes providing a direct point of contact with components of the basal transcription machinery (Wang et al., 2002). More recently, the homeobox protein, HOXB13, has been shown to interact with and suppress AR transcriptional activity and androgen-mediated prostate cancer cell growth when overexpressed in cells (Jung et al., 2004). "
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