Human Molecular Genetics, 2000, Vol. 9, No. 2 267-274
© 2000 Oxford University Press
Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length
1Department of Urology, University of Southern California—Norris Cancer Center, 2Department of Molecular Microbiology and Immunology, 3Department of Pathology, 4Department of Biochemistry and Molecular Biology and 5Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA
Normal polymorphic size variation of the exon 1 CAG microsatellite of the androgen receptor (AR) is associated with prostate cancer, benign prostatic hyperplasia and male infertility. Furthermore, abnormal expansion of the satellite leads to Kennedy’s disease. We have shown recently that the AR N-terminal domain (NTD), which contains the polyglutamine (polyQ) stretch (encoded by the CAG repeat), functionally interacts with the C-termini of p160 coactivators. In the present study we explored possible AR CAG size effects on the p160 coactivator-mediated transactivation activity of the receptor. First, we mapped the p160 coactivator interaction on the AR NTD and found an interaction surface between amino acids 351 and 537. Although this region is ‘downstream’ from the polyQ stretch, it is still within the AR NTD, is implicated in constitutive transactivation activity of the receptor, and thus might be subject to polyQ size modulation. Indeed, cotrans- fection experiments in cultured prostate epithelial cells, using AR constructs of varying CAG sizes and p160 coactivator expression vectors, revealed that increased polyQ length, up to a size of 42 repeats, inhibited both basal and coactivator-mediated AR transactivation activity. AR expression in these cells, on the other hand, was unaffected by the same increased CAG repeat size range. We conclude that the AR NTD contributes to AR transactivation activity via functional interactions with p160 coactivators and that increasing polyQ length negatively affects p160-mediated coactivation of the AR. This molecular mechanism thus might explain, at least in part, the observed phenotypic effects of the AR CAG size polymorphism.
+ To whom correspondence should be addressed at: University of Southern California—Norris Cancer Center, NOR 5421, MS 73, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Tel: +1 323 865 0631; Fax: +1 323 865 0634; Email: coetzee_g@froggy.hsc.usc.edu
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