Biology Reference
In-Depth Information
Chapter 14
Irreversible Transitions, Bistability and
Checkpoint Controls in the Eukaryotic Cell
Cycle: A Systems-Level Understanding
John J. Tyson
1
and B ´ la Nov ´k
2
1
Department of Biological Sciences, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA,
2
Centre for Integrative Systems
Biology, Department of Biochemistry, Oxford University, Oxford OX1 3QU, UK
Chapter Outline
Introduction
265
Start
275
Physiology of the Cell Cycle
265
Mitotic Checkpoint
276
Molecular Biology of the Cell Cycle
268
Irreversible Transitions in the Mammalian Cell Cycle
277
Irreversibility and Bistability
270
Additional Checkpoints
279
Irreversible Transitions in the Budding Yeast Cell Cycle
272
Conclusions
282
Two Alternative States
273
References
282
INTRODUCTION
The repetitive cycle of cell growth and division is funda-
mental to all aspects of biological growth, development and
reproduction, and defects in cell growth and division
underlie many human health problems, most notably
cancer. For these reasons, a driving ambition of molecular
cell biologists has been to discover the molecular basis of
cell cycle regulation. This goal was largely achieved in the
glory years of molecular biology (1980
e
2000), and Nobel
Prizes were duly awarded in 2001
[1
e
3]
. The end result
was an appealing vision of a 'universal' molecular mech-
anism controlling the eukaryotic cell cycle
[4]
. But the
initial appeal was quickly dispelled by a bewildering array
of interacting genes and proteins that constitute the control
system in any particular organism. For examples, see the
interaction maps of cell cycle controls in mammalian cells
[5]
and in budding yeast cells
[6,7]
. Looking closely at
these maps we can see, in places, clear connections
between some molecular interactions and certain aspects of
cell cycle progression. But can we identify any general
principles of cell cycle regulation embedded in the
network? Can we see how the gene
e
protein interactions in
any particular organism determine the unique characteris-
tics of cell proliferation in that organism?
The cell cycle is a particularly striking example of the
necessity of systems-level thinking in 21st century molec-
ular cell biology
[8]
. The resolute reductionism of the last
century, albeit necessary for identifying the molecular
components of cellular control systems and their interac-
tions with binding partners, has proved insufficient for
achieving an integrative understanding of the molecular
basis of cell physiology. Putting the pieces back together
requires new ways of thinking about and doing molecular
biology
e
an approach now known as molecular systems
biology. In this chapter, we show how systems-level
thinking reveals deep and unexpected principles of cell
cycle regulation.
Table 14.1
provides a glossary of technical terms used
in this review.
Physiology of the Cell Cycle
The cell cycle is the sequence of events whereby a growing
cell replicates all of its components and divides them more
or less evenly between two daughter cells, so that the
daughters receive all of the information and machinery
necessary to repeat the process
[9
e
11]
. The most important
components that need to be replicated and partitioned to
