Involvement of three glutamine tracts in human androgen receptor transactivation.
The androgen receptor (AR) possesses a polymorphic polyglutamine tract (polyQ), whose length is inversely correlated with its transcriptional activity. Here, we investigated whether 6 and 5 repetitive glutamine tracts (Q6 and Q5, respectively) in the N-terminal domain of AR also have effects on AR transactivation. In a reporter gene assay using two-tandem repeats of an androgen response element, deletion of glutamine tracts significantly increased AR transactivation in the following order: wild-type<a single deletion of polyQ or Q5<double deletion of polyQ and Q6<double deletion of polyQ and Q5<triple deletion. Deletion of polyQ alone or combined deletion of polyQ and Q5 from an AR mutant lacking the ligand-binding domain, which is constitutively active due to activation function-1, increased AR transactivation. However, the glutamine tracts had no influence on activation function-1 activity, suggesting that the glutamine tracts modulate the binding of AR to DNA. Q5, like polyQ, was found to be involved in the interaction between the NH(2)- and COOH-terminal regions of AR (N-C interaction). These results indicate that the inhibitory effects of polyQ and Q5 on AR transactivation are the due, at least in part, to their negative regulation of N-C interaction.
Harada
Naoki
N
Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan.
Mitani
Takakazu
T
Higashimura
Yasuki
Y
Yamaji
Ryoichi
R
Okamoto
Kazuki
K
Nakano
Yoshihisa
Y
Inui
Hiroshi
H
D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D056918:Nuclear Receptor Coactivators / Q000235:genetics; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques
D056918:Nuclear Receptor Coactivators; D010455:Peptides; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C097188:polyglutamine; D004247:DNA