Article

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

ABSTRACT

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.
    Full-text · Article · Jun 2014 · International journal of biological sciences
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    • "We provide evidence that FOXO1 directly binds to the TAU5 motif in the AR NTD. Consistent with the previous observation that the recruitment of the p160 coactivator SRC- 1 to the AR NTD is mediated through the TAU5 motif [35], we also found that SRC-1-augmented activation of truncated AR variants was abolished by expression of FOXO1. Moreover, we further showed that the physical interaction between SRC-1 and AR NTD was diminished by FOXO1. "
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    ABSTRACT: Background: Aberrant activation of the androgen receptor (AR) is a major factor highly relevant to castration-resistant progression of prostate cancer (PCa). FOXO1, a key downstream effector of PTEN, inhibits androgen-independent activation of the AR. However, the underlying mechanism remains elusive. Methods: The inhibitory effect of FOXO1 on full-length and constitutively active splice variants of the AR was examined by luciferase reporter assays and real-time reverse transcription polymerase chain reaction (RT-qPCR). In vitro protein binding assays and western blot analyses were used to determine the regions in FOXO1 and AR responsible for their interaction. Results: We found that a putative transcription repression domain in the NH2-terminus of FOXO1 is dispensable for FOXO1 inhibition of the AR. In vitro protein binding assays showed that FOXO1 binds to the transcription activation unit 5 (TAU5) motif in the AR NH2-terminal domain (NTD), a region required for recruitment of p160 activators including SRC-1. Ectopic expression of SRC-1 augmented transcriptional activity of some, but not all AR splice variants examined. Forced expression of FOXO1 blocked the effect of SRC-1 on AR variants' transcriptional activity by decreasing the binding of SRC-1 to the AR NTD. Ectopic expression of FOXO1 inhibited expression of endogenous genes activated primarily by alternatively spliced AR variants in human castration-resistant PCa 22Rv1 cells. Conclusions: FOXO1 binds to the TAU5 motif in the AR NTD and inhibits ligand-independent activation of AR splice variants, suggesting the PTEN/FOXO1 pathway as a potential therapeutic target for inhibition of aberrant AR activation and castration-resistant PCa growth.
    Full-text · Article · Jul 2013 · The Prostate
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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.
    Full-text · Article · Oct 2011
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