Consequences of supernumerary centrioles in STIL-transgenic mice

• Applicant: Professor Dr. Alwin Krämer
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 286748964

Centrosomes consist of a pair of centrioles and act as the major microtubule-organizing centers of animal cells. Centriole duplication is precisely controlled so that mitotic cells have exactly two centrosomes which direct the formation of bipolar spindles, a process essential for accurate chromosome segregation. Supernumerary centrosomes are a hallmark of cancer cells and have been postulated to contribute to tumorigenesis, perhaps by promoting chromosomal instability (CIN). In mammalian cells, centriole replication is controlled by only a few proteins, one of them being STIL, whose overexpression leads to centriole overproduction with subsequent CIN in vitro. Whether or not supernumerary centrosomes cause CIN and subsequent tumor formation in vivo is still elusive. In order to investigate the consequences of centriole overproduction in vivo, we have generated a mouse model, where the centriole replication protein STIL is overexpressed in a conditional manner. These mice will allow to examine the contribution of both supernumerary centrosomes and CIN to tumor formation and/or progression in different organ systems and genetic backgrounds. Also, the mechanisms by which extra centrioles lead to CIN in vivo can be examined. Finally, if STIL-overexpressing mice develop malignancies, then these animal are well suited as a preclinical model to study the efficacy of novel CIN- and centrosome-targeting anti-cancer drugs.

• DFG Programme: Research Grants