Abstract
Expansion of a polyglutamine-encoding trinucleotide CAG repeat in the androgen receptor (AR) to more than 37 repeats is responsible for the X-linked neuromuscular disease spinal and bulbar muscular atrophy (SBMA). Here we evaluated the effect of polyglutamine length on AR function in Xenopus oocytes. This allowed us to correlate the nuclear AR concentration to its capacity for specific DNA binding and transcription activation in vivo. AR variants with polyglutamine tracts containing either 25 or 64 residues were expressed in Xenopus oocytes by cytoplasmic injection of the corresponding mRNAs. The intranuclear AR concentration was monitored in isolated nuclei and related to specific DNA binding as well as transcriptional induction from the hormone response element in the mouse mammary tumor virus (MMTV) promoter. The expanded AR with 64 glutamines had increased capacity for specific DNA binding and a reduced capacity for transcriptional induction as related to its DNA binding activity. The possible mechanism behind these polyglutamine-induced alterations in AR function is discussed.
Highlights
Androgenic hormones play a vital role in many biological processes in various parts of the body including reproductive organs, kidney, liver, bone, muscle and brain
They exert their role via binding to the androgen receptor (AR), a ligand-activated steroid hormone receptor that acts as a transcription factor to control the expression of androgen-dependent genes [1]
The N-terminal transactivation domain (NTD) of the AR protein contains a polymorphic polyglutamine tract which has been linked to spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) [2], a disorder characterized by progressive neuromuscular weakness which develops when its length exceeds 37 residues [3]
Summary
Androgenic hormones play a vital role in many biological processes in various parts of the body including reproductive organs, kidney, liver, bone, muscle and brain They exert their role via binding to the androgen receptor (AR), a ligand-activated steroid hormone receptor that acts as a transcription factor to control the expression of androgen-dependent genes [1]. The DNA reporter is introduced by intranuclear injection of circular single-stranded (ss) DNA, which in our case yielded approximately 600 million gene copies of the MMTV long terminal repeat and all copies are active in terms of specific protein-DNA binding and chromatin remodeling [12]. We show that AR with a pathological polyQ tract of 64 residues (ARQ64) has increased capacity for specific DNA binding This increase did not correlate with an increase in transcription induction at the MMTV promoter.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
