PC 04. Identification and characterization of a ligandregulated nuclear export signal in androgen receptor
Prostate Cancer

PC 04. Identification and characterization of a ligandregulated nuclear export signal in androgen receptor

Yanqing Gong1, Javid A. Dar2, Junkui Ai2, Zhongcheng Xin1, Yinglu Guo1, Zhou Wang2

1Department of Urology, Peking University First Hospital; National Urological Cancer Center, Beijing, China; 2Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Prostate cancer is initially dependent on circulating androgens for growth and survival. Post androgen ablation, it recurs as castration resistant prostate cancer, and develops alternative pathways whereby the androgen receptor (AR) is inappropriately activated in the absence of androgens. In both androgen dependent and castration resistant prostate cancers, AR is transcriptionally active, so tight regulation of AR is essential.

Androgen action is mediated through the androgen receptor. AR is localized to the cytoplasm and is inactive in the absence of androgen. Upon androgen treatment, liganded AR translocates from the cytoplasm to the nucleus where it can transactivate androgen-responsive genes. So regulation of AR nuclear import and export represents an essential step in androgen action. In addition, increased expression and/or stability of AR have an increased half-life and sensitize prostate cancer cells to low levels of androgen, which represents an important mechanism leading to castration-resistant prostate cancer. Thus, understanding the mechanisms regulating AR protein synthesis and/or degradation has significant clinical relevance.

We have identified a novel putative NES, a nuclear export signal, in the LBD region of AR, termed NESAR which plays an important role in androgen-regulation of AR nuclear/ cytoplasmic shuttling. In the absence of hormone, NESAR is dominant over the NLS (nuclear localization signal), causing cytoplasmic localization of AR. In the presence of hormone, ligand binding abrogates NESAR activity, resulting in the nuclear localization of AR. Further findings showed that NESAR undergoes proteasome-dependent degradation. The association of NESAR with nuclear export and proteasomedependent degradation makes NESAR unique and will lead to new approaches to regulate AR protein levels and prostate cancer progression to castration-resistance. Besides, our studies are also important for elucidating the mechanisms regulating the protein level and subcellular localization of other steroid receptors for this ligand-regulated NES is functionally conserved.

Key words

Regulated nuclear; androgen; prostate cancer

DOI: 10.3978/j.issn.2223-4683.2012.s164

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