This project, supported by CARITRO foundation, aims to investigate the role of phosphorylation states of androgen receptor in cell toxicity. The project is led by Laura Tosatto under the supervision of IBF Director Mauro Dalla Serra.
Androgen receptor is a very important protein for the development of male characters as it is the transcription factor that senses the concentration of androgens in the blood. it is associated with androgen insensitivity syndrome, a condition in which an individual carry masculine genotype shows a feminine phenotype due to the inability of the protein to bind androgens (testosterone and his metabolite di-hydrotestosterone). The protein is also associated to gain of function activity in prostate cancer, which is the most diffused type of cancer in adult males, and Spinal and Bulbar Muscular Atrophy (or Kennedy’s disease), which is associated to the expansion of a poly-Glutamine stretch in the N-terminal part of the protein, causing neuro muscular degeneration. Due to the natural organization of the protein, it is very difficult to obtain structural information of the full-length protein, and of the consequences of phosphorylation, which is its most abundant post-translational modification. Some phosphorylations are known to increase cell viability and transcriptional activity of the protein, while others increase toxicity in Kennedy’s disease cell models. Transcriptional dysregulation is communal between cancer and Kennedy’s disease, and the project aims to fill the gap of knowledge on structural and functional consequences of phosphorylation of androgen receptor, engaging a multidisciplinary approach involving Institute of Biophysics, the Department CIBIO (University of Trento), the Department of Biomedical Sciences (University of Padova) and the Institute for Research in Biomedicine in Barcelona, Catalunya.
The project recently obtained further funding from Kennedy’s Disease Association (https://kennedysdisease.org).