Steroid Receptors and SUMO Modifications in the Regulation of Gene Networks and Cellular Plasticity
In-depth understanding of the function and the regulation of transcription factors (TFs) is of utmost importance in the understanding how cellular signals, such as steroid hormones, program gene expression and thereby cell physiology. We study steroid receptors, androgen receptor (AR) and glucocorticoid receptor (GR), as our main model TFs. They are ligand/steroid-controlled TFs and important drug targets. These small-molecule drugs inhibit or induce transcription. Targeting of the AR is exploited in prostate cancer therapy. Glucocorticoids are among the key drugs for treating diseases ranging from hematological cancers to inflammatory states.
Transcriptional regulation of gene networks by steroids not only involves binding of their receptors to specific DNA elements, but also critical interaction with coregulator proteins and crosstalk with other TFs. The coregulator proteins often mediate or catalyze post-translational modifications (PTMs), lysine PTMs acetylation and methylation in particular. The PTMs target both TFs and chromatin proteins, eliciting dynamic changes in the TF activity and chromatin structure. SUMOylation, a conserved lysine PTM, has emerged as an important regulatory mechanism in transcription, genomic integrity and cellular homeostasis. It appears to act as an early defence mechanism against protein-damaging stresses and an important regulator of cellular plasticity.