BBB seminar: Eckardt Treuter
Coregulatory actions of the ubiquitin system in steroidogenesis
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge/Stockholm, Sweden
Multiple signalling events control steroidogenesis in the developing and adult adrenal cortex, and the causes of adrenal insufficiency are diverse. Steroidogenic factor SF-1 (NR5A1) and its corepressor DAX-1 (NR0B1) are established transcriptional regulators of adrenal development and steroidogenic enzyme gene expression. This is supported experimentally and genetically, as mutations in both SF-1 and DAX-1 are associated with adrenal insufficiency and hypoplasia as well as gonadal dysfunction. The interplay between SF-1 and DAX-1 can be considered as central, presumably ligand-independent, signalling network in adrenogonadal development and function, raising a substantial interest in identifying additional components of the network as well as regulatory signals involved. Our research has focused in recent years on the investigation of DAX-1 and functionally related corepressors that regulate nuclear receptor transcriptional pathways in diverse metabolic and reproductive processes. Following a brief summary of this research I will present ongoing studies that characterize a novel E3 ubiquitin ligase as a regulatory component of the SF-1/DAX-1 network. We demonstrate that manipulating E3 ubiquitin ligase levels and functions specifically effects the expression of key steroidogenic enzymes such as steroidogenic acute regulatory (StAR) protein as well as cytochrome P450 aromatase (CYP19) in human adrenocortical carcinoma cells. We further provide evidence that these effects are presumably a consequence of direct E3 actions on DAX-1 and involve ubiquitination events triggering non-proteolytic pathways. The findings illustrate how distinct components of the ubiquitin system have acquired co-regulatory functions in nuclear receptor signalling pathways. In our particular case, these components may have to be included in the list of candidate factors associated with adrenal and gonadal dysfunction.
Host: Gunnar Mellgren, Institute of Medicine