Accession Number:

ADA439257

Title:

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

Descriptive Note:

Annual rept. 1 Apr 2004-31 Mar 2005

Corporate Author:

KATHOLIEKE UNIV RESEARCH AND DEVELOPMENT LEUVEN (BELGIUM)

Personal Author(s):

Report Date:

2005-05-01

Pagination or Media Count:

44.0

Abstract:

The androgen receptor binds inverted repeats as well as direct repeats of the 5-AGAACA-3 core element. The inverted repeats are called classic AREs, the direct repeats selective AREs. We found recently that the progesterone receptor is also able to transactivate through direct repeat elements, but since progesterone concentration in male serum is low, and since the ARE are found in androgen-responsive genes, the elements can still be called AR-selective. In collaboration with the group of Daniel Gewirth DAMD17-01-1-0050 we were able to solve the crystal structure of the AR DNA-binding domain bound to a direct repeat. The data indicate a stronger dimerization interface between the two AR protomers bound to the direct repeat in a unexpected head-to-head conformation. Our functional analyses after introduction of mutations in AR as well as GR do not corroborate the structural data. Further mutation analysis of the CIF is being done. A carboxyterminal extension of the DNA binding domain of the AR is known to be involved in DNA binding unfortunately its structure remains unsolved, in nuclear localization and in transactivation control. Surprisingly, deletions which affect DNA binding negatively have a positive effect on transactivation when tested in full size receptors. We have analyzed the effect of the deletion on the two activation functions of the AR. In conclusion, we observed an increased stability of the AR upon deletion of the CTE, but this is not perfectly correlated with an increased androgen response. Point mutations in the hinge can partially mimic the effect of deletion. The lysines in the hinge seem to be major signal input residues, but their exact roles are specific for each lysine degradation control versus transactivation control andor nuclear localization. Further research is aiming to discriminate these.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE