Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length

Abstract

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.

The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case-control study and meta-analysis

“…Normal CAG repeat number varies from 11 to 36 [9]. Previous studies in vitro have demonstrated that CAG repeat number shows an inverse correlation with AR activity [9][10][11][12][13][14]. Hence, it's not difficult to understand that shorter CAG repeats, increasing AR activity, are associated with prostate cancer [15,16], hirsutism [17] and hyperandrogenism in ovary [18,19], while longer CAG repeats, decreasing AR activity, are related to hypoandrogenicity [20] and male infertility due to impaired sperm production [10,21].…”

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…Across species, CAG repeat number has apparently increased along the lineage leading from basal primates to humans [29], which suggests that repeat length increases with lifespan across primates. Repeat length has been demonstrated to have a negative correlation with transactivation function [25,30], which is apparently due to a negative effect of repeat length on p160-mediated coactivation [31]. Recently, transgenic manipulations of CAG repeat length in a mouse model has experimentally demonstrated a negative correlation between repeat length and prostate cancer risk [32].…”

Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

“…Upon androgen binding, AR undergoes conformational change, translocates into the nucleus, and recruits coactivator complexes for transactivation through direct DNA binding to androgen response elements (AREs) in AR target gene promoters (9,10). As observed in wild-type AR, polyQ-AR mutants reportedly translocate into the nucleus and recruit coactivator complexes to the AREs in a liganddependent manner (11).…”