Interplay between two hormone-independent activation domains in the androgen receptor

Catholic University of Louvain, Лувен-ла-Нев, Walloon, Belgium
Cancer Research (Impact Factor: 9.33). 02/2006; 66(1):543-53. DOI: 10.1158/0008-5472.CAN-05-2389
Source: PubMed


The androgen receptor (AR) plays a key role in prostate cancer development, as well as its treatments, even for the hormone-refractory state. Here, we report that an earlier described lysine-to-arginine mutation at position 179 in AR leads to a more potent AR. We show that two activation domains (Tau-1 and Tau-5) are necessary and sufficient for the full activity of AR and the intrinsic activity of the AR-NTD. Two alpha-helices surrounding the Lys179 define the core of Tau-1, which can act as an autonomous activation function, independent of p160 coactivators. Furthermore, we show that although the recruitment of p160 coactivators is mediated through Tau-5, this event is attenuated by core Tau-1. This better definition of the mechanisms of action of both Tau-1 and Tau-5 is instrumental for the design of alternative therapeutic strategies against prostate cancer.

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    • "The transcription activation unit 5 (TAU5) motif in the AR NH2-terminal domain (NTD) interacts with AR coactivators such as the p160 family protein SRC-159. The TAU5 motif is important for androgen independent activation of the AR 60. "
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    ABSTRACT: Androgens and the androgen receptor (AR) are essential for growth and differentiation of the normal prostate gland as well as proliferation and survival of prostate cancer (PCa). Increasing evidence suggests that reactivation of the AR plays a pivotal role in disease progression to castration-resistant PCa (CRPC). Forkhead box (FOX) factors exert two distinct effects on AR function in PCa. The A-class of FOX proteins, especially FOXA1, functions as a pioneer factor to facilitate AR transactivation and PCa growth. In contrast, the O-class of FOX proteins such as FOXO1 and FOXO3, which are downstream effectors of the PTEN tumor suppressor, inhibit the transcriptional activity of either full-length AR or constitutively active splice variants of AR in a direct or indirect manner in PCa. FOXO1 also contributes to taxane-mediated inhibition of the AR and CRPC growth. Therefore, FOX family members not only have a tight relationship with AR, but also represent a pivotal group of proteins to be targeted for PCa therapy. The present review focuses primarily on recent advances in the epigenetic, mechanistic and clinical relevant aspects of regulation of the AR by FOXA1 and FOXO1 factors in PCa.
    International journal of biological sciences 06/2014; 10(6):614-619. DOI:10.7150/ijbs.8389 · 4.51 Impact Factor
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    • "Unlike the LBD of other nuclear receptors, the AR LBD displays very weak ligand-dependent transcriptional activity unless stimulated by p160 coactivators such as steroid receptor coactivator (SRC)-1 or SRC-2 [19] [20]. This is in absolute contrast to the potent inherent transcriptional activity of an isolated AR NTD fragment [20] [21] [22]. The transcriptional activity of most steroid hormone receptors is predominantly through the activation function AF-2 region in the LBD. "
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    ABSTRACT: Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR), a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC). Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.
    10/2011; 2011(2090-3111):918707. DOI:10.1155/2011/918707
    • "The NTD also harbors transcriptional activation function (AF)-1, which encompasses two transcriptional activation units (TAU): TAU-1 and TAU-5.[26] The core domain mediating TAU1 transcriptional activity has been mapped to a discreet 178LKDIL182 motif within the NTD.[2728] However, TAU5 is responsible for the majority of constitutive transcriptional activity within the NTD, and is mediated through the core sequence 435WHTLF439, accounting for approximately 50% aberrant AR activity in CRPC cells.[29] "
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    ABSTRACT: The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined.
    Journal of Carcinogenesis 08/2011; 10(1):20. DOI:10.4103/1477-3163.83937
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