Research interest
The goal of our laboratory is to understand how mitosis works, both in normal and in cancer cells. Our main interests are to reveal the roles of Cyclin-Cdk’s in mitotic progression and to decipher the regulation of protein destruction in mitosis, critical to coordinate cell division and sister chromatid separation. Using mammalian cells as model systems, we continue to develop and apply a combinatorial approach of biochemistry, RNAi-genetics and live cell imaging.
An important object of study is the control of mitotic protein destruction by a multi-subunit Ubiquitin ligase, the Anaphase-Promoting Complex or Cyclosome (APC/C) and the unknown role of its activator Cdc20 in this process. Our recent work revealed unexpected roles for the potentially oncogenic Cks protein family in directing Cdc20-dependent destruction of Cyclin A, and in coordinating the concurrent destruction of Cyclin B1 and Securin. We are using our new findings to learn how Cdc20 activates the APC/C but also to understand how Cdc20 could be inhibited by the mitotic spindle checkpoint. Furthermore, we think that depending on the way the APC/C is inhibited, distinct molecular programs may be activated which affect the cellular responses to a prolonged arrest in mitosis.
The next research goal will be to understand how oncogenic mutations may impinge on critical steps in mitotic entry, mitotic progression and mitotic exit, but also how they determine the way cells respond to errors in mitosis, or to anti-mitotic drugs. It is anticipated that answers to these questions could create exciting opportunities to develop novel anti-cancer drugs.
Key publications
van Leuken RJ, Clijsters L, Wolthuis RMF (2008) To cell cycle, swing the APC/C. BBA Reviews in Cancer, in press
van Leuken RJ, Luna-Vargas MP, Sixma TK, Wolthuis RMF and Medema RH (2008) Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of Aurora B. Cell Cycle (7) 17, in press.
Wolthuis R, Clay-Farrace L, van Zon W, Yekezare M, Koop L, Ogink J, Medema R and Pines J. (2008) Cdc20 and Cks Direct the Spindle Checkpoint-Independent Destruction of Cyclin A. Mol. Cell, Vol 30, 290-302, 09 May 2008.
Lindqvist A, van Zon W, Karlsson Rosenthal C, Wolthuis RMF. (2007) Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression. PLoS Biology 2007, 5(5):e123.
Lens SMA, Wolthuis RMF, Klompmaker R, Kauw J, Agami R, Brummelkamp T, Kops GJPL, Medema RH. (2003) Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO Journal 2003, 22: 2934-2947.
More publications by Rob Wolthuis on Pubmed
Biographic sketch
Rob Wolthuis received his Ph.D. in 1997 from the University of Utrecht, where he studied the small GTPase Ras and discovered a new Ras effector pathway. After his PhD, he started to work on mitosis, which he considers to be the most critical part of the cell cycle. He worked as a post-doctoral fellow in the laboratory of Dr. Jonathon Pines at Gurdon Wellcome/CR-UK Institute in Cambridge, UK, where he studied the role of the Cks Cyclin-Cdk subunits. Here, he also learnt how to study the regulation of protein destruction in live cells by time-lapse fluorescence microscopy. After moving to the lab of Dr. René Medema at the NKI, he invested in setting up a combinatorial approach of RNAi genetics, biochemical assays of synchronized cells and live-cell imaging to study mitosis in normal and transformed human cells. As an independent group leader, he now particularly uses this approach to study what he thinks are perhaps the most interesting players in the control of cell division: Cyclin B1-Cdk1 and the APC/C.
Co-workers
Wouter van Zon Graduate student
Linda Clijsters Graduate student
Erik Voets Graduate student
Janneke Ogink Technical staff
Bas ter Riet Technical staff
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