Endocrine Abstracts

Covalent modifications offer an efficient and fast means to modulate protein function. They play a key role in the regulation of steroid receptor-dependent transcription by remodeling the chromatin structural proteins. Steroid receptor coregulator proteins, coactivators and corepressors, which function as signaling intermediates between receptors and chromatin or transcription machinery, often possess or recruit activities that catalyze covalent lysine modifications, such as acetylation, methylation, ubiquitination and sumoylation. Several coactivators possess inherent acetyl- or methyltransferase activity or ability to recruit these activities, whereas the function of corepressors often involves the opposite activities – deacetylation and demethylation. Chromatin immunoprecipitation studies have revealed that transcriptional activation by steroid receptors, such as androgen receptor (AR), is accompanied by a cascade of distinct histone modifications and that agonists and antagonists bring about differential recruitment of histone-modifying protein complexes. In addition to the interaction with coregulator proteins, covalent modifications of steroid receptors appear to play an important modulatory role in steroid signaling. These modifications may influence the receptors’ function by altering protein-protein interactions, subcellular trafficking, intranuclear targeting, coactivator recruitment and protein degradation. Steroid receptors are ubiquitinated and degraded in the ubiquitin-proteasome system (UPS). Moreover, components of the UPS are recruited to steroid-regulated promoters, and transcription complex assembly on the promoters is dependent on the proteasome activity. Steroid receptors are also modified by small ubiquitin-related modifier proteins (SUMOs). Sumoylation targets specific lysine residues on the receptors’ N-terminal domains and inhibits their transactivation activity, especially on promoters harboring multiple response elements. Our research has recently focused on the role of lysine modifications in steroid receptor-dependent transcription. The significance of these modifications in the context of androgen action will be discussed.