A coregulatory role for the TRAP-Mediator complex in androgen receptor-mediated gene expression
ABSTRACT 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.
- SourceAvailable from: Yeqing Angela Yang
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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 "
ABSTRACT: In recent years, facilitated by rapid technological advances, we are becoming more adept at probing the molecular processes, which take place in the nucleus, that are crucial for the hierarchical regulation and organization of chromatin architecture. With an unprecedented level of resolution, a detailed atlas of chromosomal structures (histone displacement, variants, modifications, chromosome territories, and DNA looping) and mechanisms underlying their establishment, provides invaluable insight into physiological as well as pathological phenomena. In this review, we will focus on prostate cancer, a prevalent malignancy in men worldwide, and for which a curative treatment strategy is yet to be attained. We aim to catalog the most frequently observed oncogenic alterations associated with chromatin conformation, while emphasizing the TMPRSS2-ERG fusion, which is found in more than one-half of prostate cancer patients and its functions in compromising the chromatin landscape in prostate cancer.The Application of Clinical Genetics 05/2014; 7:81-91. DOI:10.2147/TACG.S35598
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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). "
ABSTRACT: HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells, HOXB13 is a key determinant of the response to androgens. Specifically, it was determined that HOXB13 interacts with the DNA-binding domain of AR and inhibits the transcription of genes that contain an androgen-response element (ARE). In contrast, the AR:HOXB13 complex confers androgen responsiveness to promoters that contain a specific HOXB13-response element. Further, HOXB13 and AR synergize to enhance the transcription of genes that contain a HOX element juxtaposed to an ARE. The profound effects of HOXB13 knockdown on androgen-regulated proliferation, migration, and lipogenesis in prostate cancer cells highlight the importance of the observed changes in gene expression.Molecular cell 11/2009; 36(3):405-16. DOI:10.1016/j.molcel.2009.10.020 · 14.02 Impact Factor
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- "Western blots were performed as previously described (Wang et al., 2002). Antibodies used are available in the Supplemental Experimental Procedures. "
ABSTRACT: The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.Cell 08/2009; 138(2):245-56. DOI:10.1016/j.cell.2009.04.056 · 32.24 Impact Factor