Nuclear Transport of Androgen Receptor

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The central hypothesis of this Project is that the mechanisms that control compartmentalization and function of the androgen receptor (AR) are improperly regulated in prostate cancer. Nuclear import and export have emerged as key mechanisms for controlling the activity of transcription factors. Nuclear import of AR is thought to be linked to androgen binding, whereby a conformational change in AR is proposed to cause chaperone release and exposure of the nuclear localization signal (NLS) to the nuclear import machinery. Few molecular details about this import pathway have been directly analyzed in normal or cancer cells, including what import receptor contacts the NLS, and how AR undergoes androgen-independent import. Nuclear export of AR is also poorly understood, though we have identified a nuclear export signal for AR, and in our preliminary studies we have found that nuclear export of AR is tightly controlled. We found that androgen-dependent phosphorylation of Ser650 in the hinge region of AR is necessary for export to the cytoplasm. We also have a biochemical assay for AR export from LNCaP cell nuclei. AR export in vitro is okadaic acid-sensitive and cytosolic factor-dependent. In Aims 1 and 2 we will identify the components that mediate AR trafficking between the cytoplasm and nucleus, and determine if alterations in the nuclear transport of AR is correlated with the progression to androgen-independence. In Aim 3 we will characterize how signal transduction pathways regulate nuclear export of AR. The AR regulates gene expression in the prostate in both normal and pathophysiological states and serves as an important target for chemotherapy. The progression of prostate cancer from androgen-dependence to androgen-independence is correlated with enhanced growth factor signaling to AR, which we propose influences AR activity through one or more transportbased mechanisms.