Centre for Cancer Biomedicine (CCB) welcomes you to a Welcome to our CCB minisymposium on Centrosome and Cilia Biology scheduled for Thursday 26th of March.
Speakers: Prof. Tim Stearns, Stanford University, and Prof. Rachel Giles, University Medical Center Utrecht
Time and place: March 26, 2015 02:15 PM - 04:15 PM, Auditorium, New research building, the Norwegian Radium Hospital
14.15 hrs: Prof. Tim Stearns, Department of Biology, Stanford University
Cilia, Centrosomes and Cell Polarity
Abstract: Tubulins are a conserved superfamily of proteins that are important in the structure and function of the microtubule cytoskeleton. Alpha-tubulin and beta-tubulin make up the microtubule polymer, and gamma-tubulin is important for nucleation of the polymer. These three tubulins are absolutely conserved in eukaryotes. In contrast, delta-tubulin and epsilon-tubulin have been lost in several branches of the eukaryotic tree. We have found that there is a sixth tubulin superfamily member, zeta-tubulin, that with delta- and epsilon-tubulin makes an evolutionarily co-conserved module. Zeta-tubulin is missing from humans, although present in marsupial mammals and other vertebrates. We have characterized zeta-tubulin in Xenopus, and find that depletion of zeta-tubulin in Xenopus embryos results in disorganization of basal body distribution and polarity in multiciliated cells, but no apparent phenotypes in other cell types. Zeta-tubulin and epsilon-tubulin localize to the basal foot in these cells, a centriole appendage that is involved in orienting the centrioles. In contrast with multiciliated cells, zeta-tubulin in cycling cells does not localize to centrioles and instead is associated with the TRiC-CCT complex, a large cytoplasmic chaperone that is responsible for folding actin, tubulin, and other proteins. We conclude that zeta-tubulin enables the basal bodies of differentiated cells to orient with respect to the cell and tissue axes. Our results suggest that zeta-tubulin function is shared with delta- and epsilon-tubulins, and thus has brought us closer to understanding the function of the tubulin superfamily as a whole.
15:00 hrs: Prof. Rachel Giles, Department of Nephrology and Hypertension, UMC Utrecht
Are cystic kidneys (replication) stressed out?
Abstract: The most common gene mutated in juvenile ciliopathy syndromes associated with renal cysts and premature renal failure is centrosomal protein CEP290. Here we demonstrate that reduction of cellular CEP290/Cep290 in primary human and mouse kidney cells leads to enhanced DNA damage signalling and accumulation of DNA breaks ex vivo and in vivo. Supernumerary centrioles, decreased replication fork velocity and fork asymmetry were detected in Cep290 mouse primary kidney knockout cells compared to wild type cells. Furthermore, we observed enhanced cyclin-dependent kinase (CDK) activity in these cells, possibly contributing to the upregulated DNA damage response. Treating Cep290 deficient cells with CDK inhibitors rescues DNA damage; moreover, we find that the primary cilia loss resulting from Cep290 dysfunction in 3D cell culture spheroids of primary kidney cells can be rescued by CDK inhibitors. We conclude that CEP290 links DNA replication stress to a wide range of ciliopathy syndromes.
15:45 hrs: Refreshments and discussions in the lobby