There is experimental evidence that inhibition of the glycogen synthase kinase-3β (GSK-3β) by small molecule inhibitors induces a rapid, CRM1/XPO1-dependent nuclear export of the AR protein in human prostate cancer cell lines. By contrast nucleo-cytoplasmic shuttling of Q641X, a C-terminally truncated AR-mutant, remains unaffected by GSK-3β inhibition. In silico analysis of the AR C-terminus (amino acids [aa] 641-920) predicted two putative NES-sites, located between aa 790-840 of the human AR. Using site-directed mutagenesis we were able to identify 3 aa involved in XPO1/CRM1 mediated nuclear export of the AR. A comparative analysis of the resulting NES peptide sequence showed that it is evolutionary highly conserved among vertebrate species (fish, amphibia, modern sauropsida, mammalia). The latter suggests that this NES plays an important role in the regulation of AR-function and/or signaling.
Presenting author: Marcus Cronauer, Department of Urology, UKSH Campus Lübeck, Lübeck, Germany. Email: email@example.com.