SCF ubiquitin ligases, cell cycle, transcription and cancer development – Olle Sangfelt's Group

Our research is focused on how protein ubiquitylation control cellular integrity and how alterations of components of the ubiquitin-machinery contribute to cancer development and progression.

Five people standing next to each other smiling infront of the camera for a group photo.
Olle Sangfelt's group, Aljona Malyukova, Olle Sangfelt, Andrä Brunner, Samuele Fisicaro, David Lee Photo: N/A

Under normal growth conditions the activity of proteins is tightly regulated to ensure proper cellular homeostasis. Proteins undergo extensive post-translational modifications (PTMs) that control their stability and/or interaction with other proteins, as well as with RNA and DNA molecules. One specific type of PTM is the covalent attachment of the small protein ubiquitin (Ub), in a process known as ubiquitylation. Our research is focused on how deregulation of the ubiquitin-machinery contributes to cancer development and drug resistance.

Ubiquitylation is executed through an enzymatic multistep reaction involving E1-activating, E2-conjugating, and E3 ubiquitin ligases responsible for target substrate recognition. Importantly, protein ubiquitylation and proteasomal degradation is counteracted by deubiquitylating enzymes (DUBs), highlighting the reversibility of the system, analogous to that of kinase-phosphatase activities catalyzing protein phosphorylation-dephosphorylation reactions. A wealth of experimental evidence demonstrates that phosphorylation and ubiquitylation are interconnected processes which open up diverse opportunities to target the ubiquitin-system in cancer.

We postulate that specific SCF E3 ubiquitin ligases, through targeted degradation of oncogenic substrates, function as key regulators of several tumor-supportive cellular programs, potential predictive markers and targets for therapeutic intervention. The projects are focused on characterization of FBW7, FBXL12 and FBXO28, their regulatory functions during replication stress, checkpoint activation/recovery and identification of novel drugs targeting these SCF ubiquitin ligases.

Publications

Selected publications