Laurence Calzone
Post-doc
Projet Contraintes
INRIA Rocquencourt
Domaine de Voluceau B.P. 105
78153 Le Chesnay Cedex
France
Laurence.Calzone#inria.fr
Research interests
The budding yeast cell cycle :
The budding yeast cell cycle has attracted many experimentalists over
the years for its simplicity and facility to manipulate genetically.
The regulatory components described in the budding yeast, Saccharomyces
cerevisiae, are conserved in higher eukaryotes. The budding yeast
is governed by a complex network of chemical reactions controlling the
activity of the cyclin-dependent kinases (CDKs), proteins that drive
the major events of the cell cycle. The presence of these proteins is
required for the transition from G1 to S phase (Start) whereas their
absence permits the transition from S/M to G1 phase (Finish). The cell
cycle of the budding yeast is based on the alternation between these
two states. However, the complexity of this network is such that it
requires mathematical tools in order to test the accuracy of the theory
based on the experiments. We built and transcribed a hypothetical
molecular mechanism of the budding yeast into differential equations
and a corresponding parameter set illustrating the main events of the
cell cycle such as: the synthesis of cyclins (Cln1,2; Cln3; Clb1,2;
Clb5,6) by their transcription factors (SBF, Mcm1, MBF); their
association with stoichiometric inhibitors (Sic1, Cdc6); their
degradation by SCF and adaptors of the APC (Cdc20, Cdh1). The emphasis
was put on mechanisms responsible for the release of Cdc14 from the
RENT complex, Cdc14 being the major player in exit from mitosis. The
wild type cells and more than 100 mutants showed phenotypes in
accordance with the experimental results. From these results, some
mutants defective in the Start and Finish transitions and the different
ways to rescue them can be simulated as well. An interactive page web
describing the model is available at http://mpf.biol.vt.edu/
The model is presented in Molecular Biology of the Cell - [Abstract] [Article]
The drosophila early cell cycles :
Previous studies on modeling of budding yeast (Saccharomyces
cerevisiae), fission yeast (Schizosaccharomyces pombe) or mammalian
cells have described in details the mechanisms of cell cycle
regulation. Drosophila melanogaster cell cycle, although comparable,
presents interesting challenges. In Drosophila embryogenesis, different
types of cell cycles are observed. One of them, immediately following
fertilization, is characterized by thirteen syncytial cycles during
which only nuclear divisions occur, rapidly and synchronously. These
cycles, driven by maternal genes, are alternating between S and M
phases. Although division cycles are observed, almost no oscillation in
total level of B-cyclins (CycB) is recorded, suggesting a local
degradation of these cyclins. Based on a previous mathematical model of
Xenopus cell cycles, a tentative model is built to describe the
Drosophila melanogaster division cycles in early developmental stages.
This study is in progress.
Modeling in BIOCHAM:
BIOCHAM (the BIOCHemical Abstract Machine) is a programming language
for modeling biochemical systems. It is based on two aspects:
(1) the analysis and simulation of boolean, kinetic and stochastic
models and (2) the formalization of biological properties in temporal
logic (CTL and LTL with constraints).
This language allows to analyze,
verify and query the structure of the model, and find appropriate
values of the parameters to obtain a specific behavior of the system.
For example, it is possible to find one or several parameter values
that reproduce
specific properties (e.g. the system oscillates with a period T or a protein fully activates -
its
concentration reaches a threshold value), etc
... Coupled with other methods for finding parameter values
(bifurcation diagrams ...), this search assists the modeler/biologist
in the modeling process.
The formalization of biological properties is essential
to learn or verify biochemical reaction rules in an existing model.
1. If the structure of the protein network is known (for example, Kohn,
1999), it is possible to verify that some properties are true or
conserved: the molecule X can activate at some point, or a protein X is
a checkpoint for the (in)activation of another protein Y, etc ...
2. If the model is incomplete, BIOCHAM can propose ways to complete the
model by adding or delete rules such that the model verifies the set of
CTL formulae (called specification).
See BIOCHAM
webpage for more details.
For first-users of BIOCHAM, there is a tutorial
for the Graphical User Interface.
The tutorial is also available as a pdf
file.
Morphogenesis:
Protein dynamics in growth and polarity in fission yeast cells.
In progress ...