Modulation of Androgen Receptor Transcriptional Activity

Androgens, testosterone (T) and 5a-dihydrotestosterone (DHT), are important for male and female physiology, in particular for male sexual differentiation, development of secondary male characteristics and spermatogenesis. These hormones exert their actions by binding to the androgen receptor (AR), a transcription factor that belongs to the family of steroid hormone receptors (SHRs). After ligand binding, the AR migrates to the nucleus and binds to androgen response elements (AREs), which are present in the promoter and enhancer regions of androgen regulated genes. After DNA binding, chromatin remodelling factors, other co-factors (co-activators or co-repressors) and proteins of the transcription initiation complex, including RNA polymerase II, are recruited by the AR to regulate gene transcription. Several modulating processes and factors can influence AR transactivation. Not only co-factors play a role in AR transactivation, but also post-translational mod! ifications of the AR, such as acetylation, ubiquitylation, sumoylation and phosphorylation, can modify AR transactivation. In addition, mutations in the AR gene can have dramatic consequences for AR transactivation. In general, AR mutations result in the androgen insensitivity syndrome, in which the male phenotype is affected. However, the exact influence of these modulating processes and factors is still not clear. In this thesis we focused on the influence of phosphorylation on the AR. The influence of mutation F826L on the AR activity has also been studied. Finally, it has been determined whether co-factors can be isolated with a DNA bound AR.

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