Substitution of Cys-560 by Phe, Trp, Tyr, and Ser in the first zinc finger of human androgen receptor affects hormonal sensitivity and transcriptional activation.
We have established and characterized four human androgen receptor ( AR) mutants, AR C560F, C560W, C560Y, C560S). To assess the functional significance of these substitutions, we compared the transcriptional activation, hormone binding affinity, receptor-DNA interaction, and the subcellular distribution of the hormone-receptor complexes. Binding studies showed that all mutants bound methyltrienolone (R1881) with wild type affinity (Kd = 0.5 nM). Transactivation efficiency, as compared to wild type AR, increased 150% with C560F and decreased to 70% with C560W and C560Y and to 40% with mutant C560S. Subcellular receptor distribution showed that 85% of C560F bound with hormone was extracted from the nuclear fraction and 15% in the cytosol. Gel mobility shift assays showed that C560F expressed in CV-1 cells bound to an androgen responsive element (ARE) with equal efficiency as the wild type human AR. The mutants C560W and C560Y demonstrated a lower ability to bind to ARE, whereas C560S showed a significantly lower ability to interact with ARE. We propose that the change in polarity introduced into the loop structure by C560S leads to a shorter period of contact between the mutant receptor and DNA resulting in decreased transcriptional activation levels.[1]References
- Substitution of Cys-560 by Phe, Trp, Tyr, and Ser in the first zinc finger of human androgen receptor affects hormonal sensitivity and transcriptional activation. Warriar, N., Yu, C., Pagé, N., Govindan, M.V. J. Biol. Chem. (1994) [Pubmed]
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