Accession Number:

ADA455783

Title:

The Hinge Region as a Key Regulatory Element of Androgen Receptor Dimerization, DNA Binding and Transactivation

Descriptive Note:

Final rept. 1 Apr 2002-31 Mar 2006

Corporate Author:

KATHOLIEKE UNIV RESEARCH AND DEVELOPMENT LEUVEN (BELGIUM)

Personal Author(s):

Report Date:

2006-05-01

Pagination or Media Count:

91.0

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 NC 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,

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE