Inhibition of p160-mediated coactivation with increasing androgen receptorpolyglutamine length

Normal polymorphic size variation of the exon 1 CAG microsatellite of the a ndrogen receptor (AR) is associated with prostate cancer, benign prostatic hyperplasia and male infertility, Furthermore, abnormal expansion of the sa tellite leads to Kennedy's disease. We have shown recently that the AR N-te rminal domain (NTD), which contains the polyglutamine (polyQ) stretch (enco ded by the CAG repeat), functionally interacts with the C-termini of p160 c oactivators. 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 a n 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 th us might be subject to polyQ size modulation. Indeed, cotransfection experi ments 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 coactiv ator-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 vi a functional interactions with p160 coactivators and that increasing polyQ length negatively affects p160-mediated coactivation of the AR. This molecu lar mechanism thus might explain, at least in part, the observed phenotypic effects of the AR CAG size polymorphism.