Cell Cycle Regulation

Research Interests

Our research focuses on cell cycle progression and the cytoskeleton in normal development and disease. We are particularly interested in the role played by microtubule organizing structures, such as the centrosome, cilia and flagella. The centrosome is the major microtubule organizer in animal cells, and is very often abnormal in cancer. Cilia and flagella are cellular projections which are indispensable in a variety of cellular and developmental processes including cell motility, propagation of morphogenic signals and sensory reception. Despite their importance, we know very little about centrosome and cilia biogenesis or how they may go awry in human disease. Our laboratory uses an integrated approach to study those questions: we combine studies in model organisms with studies in human cells, bioinformatics and mathematical modeling to have an integrated view of this process. The fruit fly is an excellent organism to address those questions, since it combines possibilities of screening multiple genes with the ability to perform in-depth regulation studies in the whole organism. As the regulatory mechanisms of the cell cycle and cytoskeleton have been highly conserved throughout evolution, we can extrapolate our findings to humans to test their relevance for human disease. An understanding of the pathways involved in cell cycle and cytoskeleton can generate diagnostic and prognostic markers and hopefully provide novel therapeutic targets in human disease.

Check our website at http://sites.igc.gulbenkian.pt/ccr/

Group Members

Daniela Brito	Postdoc
	Tel: 21 446 4636
Mariana Faria	Postdoc
	Tel: 21 446 636
Ana Paula Martins	External Ph.D. Student
	Tel: 21 440 7925
Filipe Leal	External Ph.D. Student
	Tel: 21 440 7925
Francisco Freixo	External Masters Student
	Tel: 21 446 6636
Paulo Duarte	Trainee
	Tel: 21 440 7925
Pedro Machado	Trainee
	Tel: 21 440 7925
Ana Isabel Cunha	Trainee
	Tel: 21 440 7900
Zita Santos	2006 PDIGC PhD Student
	Tel: 21 440 7925
Inês Ferreira	2007 PGD PhD Student
	Tel: 21 446 4514
Inês Bento	2008 PGD PhD Student
	Tel: 21 440 7925

Research Project

Regulation of the tumorigenesis-related kinase SAK/PLK4

Centrioles are subcellular structures essential for the formation of cilia, flagella and centrosomes. Misregulation of centriole biogenesis is associated with human disorders such as retinal degeneration, infertility, cystic kidney disease and cancer. Despite their importance, very little is known about the control of centriole biogenesis. This project aims at a better understanding of the mechanisms of centriole duplication and how centriole number is controlled. Our previous studies have shown that SAK kinase is an essential player in centriole duplication. Absence of this kinase leads to absence of centriole duplication, while overexpression leads to an increase in the number of centrioles both in human and Drosophila tissue culture cells. Our findings offer us an entry point to study the regulation of centriole number. This project will use a combination of genetic, biochemical and cell biology approaches in Drosophila melanogaster to understand how SAK is regulated by the SCF/Slimb complex. Studies in Drosophila have proven fruitful in identifying enzymes involved in cell cycle and centrosome function, some of which are now being targeted for the treatment of cancer in humans. SAK has also been shown to be involved in tumorigenesis in mice and humans. This project will lead to novel mechanisms involved in centriole duplication and possibly tumorigenesis that this group will pursue in the future using Drosophila and human tissue culture cells.

Funding

Fundação para a Ciência e a Tecnologia (FCT) Project Grant, Portugal

Collaborators

Department of Genetics, University of Cambridge, UK
David Glover

Research Project

Regulation of Centriole Biogenesis and Function: an Integrative Approach

Centrioles are important structures in eukaryotic cells. They organize the centrosome, which is the primary microtubule organizing centre in animal cells; and they function as basal bodies, which template the formation of flagella and cilia. However, little is known about the assembly of these structures. It is therefore important to map components and regulators of centriole derived structures (CDS) in organisms where functional studies are possible. Here we propose to join efforts of an experimental laboratory (Monica Bettencourt-Dias), which has experience in the use of genome-wide RNAi strategies and in the study of centriole biogenesis, and a bioinformatics laboratory (Jose Pereira-Leal) which has experience in the study of the evolution of proteins and data mining, to follow complementary approaches in the study of the biogenesis of centrioles and basal bodies. Computational and functional genomic strategies have proven to be very useful in finding novel components of CDS. Here we aim to find novel regulators in centriole biogenesis by using a combined strategy: on one hand we will focus on a major regulator of centriole duplication, SAS-6, and use experimental and bioinformatics approaches that we have developed to understand its function and to find novel regulators of its activity; on the other hand we will use data mining combined with computational genomics to create a list of candidate components and regulators of CDS. This work will give us a better understanding of centriole biogenesis and how this process may go awry in human disease.

Funding

Fundação para a Ciência e a Tecnologia (FCT) Project Grant, Portugal

Collaborators

Departmente of Cell Biology, Genetics and Development, University fo Minnesota, USA
Ryoko Kuriyama

Research Project

Regulation of Centriole Assembly

The centrosome is the primary microtubule organizing centre (MTOC) in animal cells. It includes two centrioles, which act as a core structure and can also function as basal bodies to grow flagella or cilia. Recent studies, including ours, have identified a group of conserved proteins which give us an entry point to those questions. The assembly programme starts with recruitment of SAK, a kinase involved in tumorigenesis, to the mother centriole. This allows recruitment of SAS-6 and SAS-4, two coiled-coil molecules necessary for the formation of a “centriole scaffold” and recruitment of centriolar MTs, respectively. How those molecules organise microtubules to form a centriole is not known. Here we will search for molecular interactors of those proteins. Additionally, we test the possibility that those proteins may directly or indirectly lead to centriole assembly through post-translational modifications (PTM) of tubulin. We are also further studying the role of SAK in centriole assembly using Xenopus extracts in collaboration with Eric Karsenti.

Funding

EMBO Installation Grant, European Molecular Biology Organisation (EMBO),
Fundação para a Ciência e a Tecnologia (FCT, Portugal) and Fundação Calouste Gulbenkian (FCG, Portugal)

Collaborators

CRMB, Montpellier, France - Carsten Janke
EMBL, Heidelberg, Germany - Eric Karsenti

Publications

(Selected) Updated January (2009).

Cunha-Ferreira I, Rodrigues-Martins A, Bento I, Riparbelli M, Zhang W, Laue E, Callaini G, Glover D, and Bettencourt Dias, M. (2009). The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4 Current Biology

Bettencourt Dias, M & Zita Carvalho-Santos (2008). The double life of centrioles: CP110 hits the spotlight Trends in Cell Biology, Research Focus. 18(1) :8-11

Rodrigues-Martins A, Riparbelli M, Callaini G, Glover D and Bettencourt Dias, M. (2008). From centriole biogenesis to cellular function: centrioles are essential for cell division at critical developmental stages Cell Cycle 7(1) :11-16

Rodrigues-Martins, A*, Bettencourt Dias, M*, Riparbelli, M*, C Ferreira, I Ferreira, G Callaini & DM Glover (2007). DSAS-6 organizes a tube-like centriole precursor and its absence suggests modularity in centriole assembly. Curr Biol 17(17) :1465-1472

Bettencourt Dias, M. and Glover, D.M. (2007). Centrosome Biogenesis and Function, Nature Reviews in Molecular and Cellular Biology 8(6) :451-63.

Rodrigues-Martins, A., Riparbelli, M., Callaini, G., Glover, D.M. and Bettencourt Dias, (2007). Revisiting the role of the mother centriole in centriole duplication.
Recommended by Faculty of 1000 Biology. Science 316(5827) :1046-50 Link

Bettencourt Dias, M., Rodrigues-Martins, A., Carpenter, L., Riparbelli, M., Gatt, M., Lehmann, L., Carmo, N., Balloux, F., Callaini, G., Glover, D.M. (2005). SAK/PLK4 is required for centriole duplication and flagella development. Current Biology 15(24)

Bettencourt Dias, M., Giet, R., Sinka, R., Mazumdar, A., Lock, W.G., Balloux, F., Zafiropoulos, P., Yamaguchi, S., Winter, S., Carthew, R., Cooper, M., Jones, D., Frenz, L. and Glover, D.M. (2004). Genome wide survey of protein kinases required for cell cycle progression.
Selected as a MUST READ paper by Faculty of 1000 Biology. Nature 432 :980-7 Link