The Hinge Region Regulates DNA Binding, Nuclear Translocation, and Transactivation of the Androgen Receptor

Abstract

The androgen receptor (AR) encoding gene can undergo mutations during the development and treatment of prostate cancer. Even in hormone-independent stages, mutations in the receptor paradoxically seem to result in an increased AR function. Two such point mutations have been described in the part of the AR involved in DNA binding and nuclear translocation, namely the hinge region. Despite a decreased nuclear translocation, these mutant ARs display increased transactivating potencies. Through detailed analysis of the hinge region, we found that deletion of residues 629 to 636 resulted in a stronger androgen response on different reporters, although this mutant displays an extremely low in vitro affinity for androgen response elements. This superactivity is independent of nuclear localization and can be inhibited by antiandrogens. Surprisingly, the AR activation functions, AF1 and AF2, are not dramatically affected when the inhibitory region (629-RKLKKLGN-636) is deleted, although cotransfected p160 coactivator TIF2 had a stronger potentiating effect in the absence of this motif. The liganddependent interaction between the amino-terminal domain and the ligand-binding domain (N/C interaction) plays an important role in transactivation by the AR. We found that this interaction is strongly enhanced by deletion of the inhibitory region. In conclusion, the description of prostate cancer mutations has led to the discovery of a complex role of the hinge region in nuclear localization, DNA binding, coactivator recruitment, and N/C interaction of the AR. [Cancer Res 2007;67(9):4514-23]

Regulation of the androgen receptor by post-translational modifications

“…As detailed in Table 1, this mutant AR displayed a stronger androgen response but it had low affinity for ARE binding sites, which is not surprising as these effects were independent of nuclear localisation. This deletion construct also displayed an enhanced N and C terminal interaction and could be inhibited by anti-androgen treatment (Haelens et al 2007). These findings are contradictory to the published work on AR-Ac mutants, which highlights the role of the intact hinge region in the regulation of AR activity and how PTM can influence its function.…”

Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

“…Most constructs have been previously described (13,26). GST-AR 553-635 and GST-AR 634-668 were gifts from S. Balk .…”

Structural basis for the nuclear import of the human androgen receptor

“…These substitutions did, however, attenuate both the recruitment of the GR-transcription complex and of mutant GR transactivation, implying a direct function of its hinge region on co-regulator assembly (Carrigan et al, 2007). Haelens et al, have also recently shown that AR hinge residues have a function on transactivation that is independent on other functions, such as DNA binding (Haelens et al, 2007).…”