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Effect of a short CAG (glutamine) repeat on human androgen receptor function
Dacheng Ding1, Lihua Xu, Mani Menon
1The Vattikuti Urology Institute, Henry Ford Hospital and Henry Ford Health Sciences Center, Detroit, Michigan 48202-3450, USA.
The Prostate
|December 16, 2003
Summary
Shorter CAG repeats in the androgen receptor (AR) gene, specifically 17 repeats, enhance AR transactivation activity. This suggests a 17-CAG repeat may increase prostate cancer growth and progression risk.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The androgen receptor (AR) gene exhibits CAG repeat polymorphism, with lengths varying from 11-31 repeats in the general population.
- A 17-CAG repeat in the AR gene is more prevalent in prostate cancer patients than in the general population, suggesting potential pathophysiological relevance.
- The CAG repeat encodes a polyglutamine tract within the AR protein's N-terminal transactivation domain.
Purpose of the Study:
- To investigate the functional impact of the 17-CAG repeat polymorphism in the androgen receptor (AR) gene on androgen action in prostate cancer cells.
- To test the hypothesis that a 17-CAG repeat in the AR gene may uniquely influence androgen signaling pathways relevant to prostate cancer development.
Main Methods:
- Transient transfection of DU145 cells (AR-null) with AR expression plasmids containing varying CAG repeat lengths (14-25 repeats).
- Co-transfection with an androgen-responsive reporter plasmid (PSA-luciferase) to measure AR activity.
- Quantification of AR protein levels and transactivation activity normalized to AR protein amount.
Main Results:
- CAG repeat length significantly affected AR protein levels per unit of transfected DNA (P = 0.02).
- The AR with a 17-CAG repeat exhibited 40% greater transactivation activity compared to the AR with a 21-CAG repeat (P < 0.01).
- Transactivation activity was analyzed per unit of AR protein to account for variations in protein expression.
Conclusions:
- An androgen receptor (AR) with a 17-CAG repeat demonstrates enhanced transactivation, potentially leading to more effective growth stimulation of prostate epithelial cells.
- This heightened AR activity associated with the 17-CAG repeat may contribute to the more efficient development of clinically significant prostate cancer.
- The findings highlight the role of AR CAG repeat length polymorphism in modulating prostate cancer risk and progression.