Coordination of Cell Division by Regulated Protein Destruction


Wijzig gegevens

Titel Coordination of Cell Division by Regulated Protein Destruction
Looptijd 01 / 2007 - 01 / 2012
Status Lopend
Dissertatie Ja
Onderzoeknummer OND1318569
Leverancier gegevens NKI

Samenvatting (EN)

During mitosis, the duplicated genome is irreversibly distributed over two newly formed cells. A multisubunit assemby -the Anaphase Promoting Complex or Cyclosome (APC/C)- ubiquitinates key regulatory proteins at highly defined mitotic time points. Poly-ubiquitination targets these APC/C substrates for rapid proteolysis by the 26S proteasome. Sequential degradation of APC/C substrates such as Cyclin A, Cyclin B1 and Securin orchestrates cell division with segregation of sister chromatids, essential to guarantee genomic integrity. The question remains how the APC/C recognizes a critical substrate at the right time. To address this important issue, I established an innovative, combinatorial approach of gene silencing, biochemistry and live cell imaging. Hereby, we identified a role for APC/C phosphorylation in controlling Cyclin A destruction. Furthermore, we discovered that APC3 coordinates Cyclin B1 and Securin destruction in metaphase. Our results show that individual subunits, phosphorylation events as well as the intracellular localization of APC/C-complexes contribute to substrate selection. My aim is to build a comprehensive model of how the APC/C coordinates cell division in human cells. I will focus on two central objectives: ? to reveal the contribution of individual subunits -and their regulatory domains- to specific APC/C activity; ? to identify critical determinants of substrate selection by the APC/C. In particular, we will determine complex formation between the APC/C and its substrates, and uncover spatio-temporal dynamics of the APC/C in live cells. This project will lead to the discovery and understanding of fundamental mechanisms by which the APC/C targets its substrates and coordinates cell division. It will also yield important insight into how the APC/C responds to cell cycle checkpoints. Finally, a molecular model of APC/C activity could create new opportunities to design anti-cancer drugs.

Betrokken organisaties

Betrokken personen

Projectleider Dr. R.M.F. Wolthuis
Promovendus Ing. W. van Zon


D21300 Biochemie
D21400 Genetica
D21500 Histologie, celbiologie

Ga terug naar de inhoud
Ga terug naar de site navigatie