The Hinge Region as a Key Regulatory Element of Androgen Receptor Dimerization, DNA Binding and Transactivation
Abstract
The androgen receptor (AR) gene can undergo mutations during the development and treatment of prostate cancer. Two point mutations have been described in the hinge region, which is involved in DNA binding and nuclear translocation. These mutants display increased transactivating properties, despite a decreased nuclear translocation. We therefore performed a more detailed analysis of this part of the hinge region. Deletion of residues 629 to 636 (RKLKKLGN) resulted in a stronger androgen response. Truncation studies revealed that some hinge mutants are super active, in spite of their extremely low in vitro affinity for androgen response elements. Surprisingly, the activation functions AF1 and AF2 are not dramatically affected if the inhibitory 629- RKLKKLGN-636 motif is deleted. The ligand-dependent interaction between the amino-terminal domain and the ligand-binding domain plays an important role in transactivation by the AR. This interaction is strongly enhanced by mutation of the hinge region, but even in the absence of this N/C interaction, the hinge region mutants are more active compared to wild type AR. In conclusion, the AR hinge region is more than a flexible linker between the DNA-binding domain and the ligand-binding domain. Description of prostate cancer mutations revealed that the hinge co-ordinates the AR activity by interfering with several functions such as the nuclear localization,
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2006
- Accession Number
- ADA455783
Entities
People
- Frank A. Claessens