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NOBEL PRIZE for medicine 2001
 Key
regulators of the cell cycle
Leland H. Hartwell, (photo)
R. Timothy (Tim) Hunt
and
Paul M. Nurse
All organisms consist of cells that multiply through cell
division. An adult human being has approximately 100 000 billion
cells, all originating from a single cell, the fertilized
egg cell. In adults there is also an enormous number of continuously
dividing cells replacing those dying. Before a cell can divide
it has to grow in size, duplicate its chromosomes and separate
the chromosomes for exact distribution between the two daughter
cells. These different processes are coordinated in the cell
cycle.
This year's Nobel Laureates in Physiology or Medicine have
made seminal discoveries concerning the control of the cell
cycle. They have identified key molecules that regulate the
cell cycle in all eukaryotic organisms, including yeasts,
plants, animals and human. These fundamental discoveries have
a great impact on all aspects of cell growth. Defects in cell
cycle control may lead to the type of chromosome alterations
seen in cancer cells. This may in the long term open new possibilities
for cancer treatment.
Leland Hartwell (born 1939), Fred Hutchinson Cancer
Research Center, Seattle, USA, is awarded for his discoveries
of a specific class of genes that control the cell cycle.
One of these genes called "start" was found to have a central
role in controlling the first step of each cell cycle. Hartwell
also introduced the concept "checkpoint", a valuable aid to
understanding the cell cycle.
Paul Nurse (born 1949), Imperial Cancer Research Fund,
London, identified, cloned and characterized with genetic
and molecular methods, one of the key regulators of the cell
cycle, CDK (cyclin dependent kinase). He showed that the function
of CDK was highly conserved during evolution. CDK drives the
cell through the cell cycle by chemical modification (phosphorylation)
of other proteins.
Timothy Hunt (born 1943), Imperial Cancer Research
Fund, London, is awarded for his discovery of cyclins, proteins
that regulate the CDK function. He showed that cyclins are
degraded periodically at each cell division, a mechanism proved
to be of general importance for cell cycle control.
One billion cells per gram tissue
Cells having their chromosomes located in a nucleus and separated
from the rest of the cell, so called eukaryotic cells, appeared
on earth about two billion years ago. Organisms consisting
of such cells can either be unicellular, such as yeasts and
amoebas, or multi-cellular such as plants and animals. The
human body consists of a huge number of cells, on the average
about one billion cells per gram tissue. Each cell nucleus
contains our entire hereditary material (DNA), located in
46 chromosomes (23 pairs of chromosomes). It has been known
for over one hundred years that cells multiply through division.
It is however only during the last two decades that it has
become possible to identify the molecular mechanisms that
regulate the cell cycle and thereby cell division. These fundamental
mechanisms are highly conserved through evolution and operate
in the same manner in all eukaryotic organisms.
The phases of the cell cycle
The cell cycle consists of several phases. In the first phase
(G1) the cell grows and becomes larger. When it has reached
a certain size it enters the next phase (S), in which DNA-synthesis
takes place. The cell duplicates its hereditary material (DNA-replication)
and a copy of each chromosome is formed. During the next phase
(G2) the cell checks that DNA-replication is completed and
prepares for cell division. The chromosomes are separated
(mitosis, M) and the cell divides into two daughter cells.
Through this mechanism the daughter cells receive identical
chromosome set ups. After division, the cells are back in
G1 and the cell cycle is completed. The duration of the cell
cycle varies between different cell types. In most mammalian
cells it lasts between 10 and 30 hours. Cells in the first
cell cycle phase (G1) do not always continue through the cycle.
Instead they can exit from the cell cycle and enter a resting
stage (G0).
Cell cycle control
For all living eukaryotic organisms it is essential that the
different phases of the cell cycle are precisely coordinated.
The phases must follow in correct order, and one phase must
be completed before the next phase can begin. Errors in this
coordination may lead to chromosomal alterations. Chromosomes
or parts of chromosomes may be lost, rearranged or distributed
unequally between the two daughter cells. This type of chromosome
alteration is often seen in cancer cells. It is of central
importance in the fields of biology and medicine to understand
how the cell cycle is controlled. This year's Nobel Laureates
have made seminal discoveries at the molecular level of how
the cell is driven from one phase to the next in the cell
cycle.
Cell cycle genes in yeast cells
Leland Hartwell realized already at the end of the 1960s the
possibility of studying the cell cycle with genetic methods.
He used baker's yeast, Saccharymyces cerevisiae, as a model
system, which proved to be highly suitable for cell cycle
studies. In an elegant series of experiments 1970-71, he isolated
yeast cells in which genes controlling the cell cycle were
altered (mutated). By this approach he succeeded to identify
more than one hundred genes specifically involved in cell
cycle control, so called CDC-genes (cell division cycle genes).
One of these genes, designated CDC28 by Hartwell, controls
the first step in the progression through the G1-phase of
the cell cycle, and was therefore also called "start". In
addition, Hartwell studied the sensitivity of yeast cells
to irradiation. On the basis of his findings he introduced
the concept checkpoint, which means that the cell cycle is
arrested when DNA is damaged. The purpose of this is to allow
time for DNA repair before the cell continues to the next
phase of the cycle. Later Hartwell extended the checkpoint
concept to include also controls ensuring a correct order
between the cell cycle phases.
A general principle
Paul Nurse followed Hartwell's approach in using genetic methods
for cell cycle studies. He used a different type of yeast,
Schizzosaccharomyces pombe, as a model organism. This yeast
is only distantly related to baker's yeast, since they separated
from each other during evolution more than one billion years
ago. In the middle of the 1970s, Paul Nurse discovered the
gene cdc2 in S. pombe. He showed that this gene had a key
function in the control of cell division (transition from
G2 to mitosis, M). Later he found that cdc2 had a more general
function. It was identical to the gene ("start") that Hartwell
earlier had identified in baker's yeast, controlling the transition
from G1 to S. This gene (cdc2) was thus found to regulate
different phases of the cell cycle. In 1987 Paul Nurse isolated
the corresponding gene in humans, and it was later given the
name CDK1 (cyclin dependent kinase 1). The gene encodes a
protein that is a member of a family called cyclin dependent
kinases, CDK. Nurse showed that activation of CDK is dependent
on reversible phosphorylation, i.e. that phosphate groups
are linked to or removed from proteins. On the basis of these
findings, half a dozen different CDK molecules have been found
in humans.
The discovery of the first cyclin
Tim Hunt discovered the first cyclin molecule in the early
1980s. Cyclins are proteins formed and degraded during each
cell cycle. They were named cyclins because the levels of
these proteins vary periodically during the cell cycle. The
cyclins bind to the CDK molecules, thereby regulating the
CDK activity and selecting the proteins to be phosphorylated.
The discovery of cyclin, which was made using sea urchins,
Arbacia, as a model system, was the result of Hunt's finding
that this protein was degraded periodically in the cell cycle.
Periodic protein degradation is an important general control
mechanism of the cell cycle. Tim Hunt later discovered cyclins
in other species and found that also the cyclins were conserved
during evolution. Today around ten different cyclins have
been found in humans.
The engine and the gear box of the cell cycle
The three Nobel Laureates have discovered molecular mechanisms
that regulate the cell cycle. The amount of CDK-molecules
is constant during the cell cycle, but their activities vary
because of the regulatory function of the cyclins. CDK and
cyclin together drive the cell from one cell cycle phase to
the next. The CDK-molecules can be compared with an engine
and the cyclins with a gear box controlling whether the engine
will run in the idling state or drive the cell forward in
the cell cycle.
A great impact of the discoveries
Most biomedical research areas will benefit from these basic
discoveries, which may result in broad applications within
many different fields. The discoveries are important in understanding
how chromosomal instability develops in cancer cells, i.e.
how parts of chromosomes are rearranged, lost or distributed
unequally between daughter cells. It is likely that such chromosome
alterations are the result of defective cell cycle control.
It has been shown that genes for CDK-molecules and cyclins
can function as oncogenes. CDK-molecules and cyclins also
collaborate with the products of tumour suppressor genes (e.g.
p53 and Rb) during the cell cycle. The findings in the cell
cycle field are about to be applied to tumour diagnostics.
Increased levels of CDK-molecules and cyclins are sometimes
found in human tumours, such as breast cancer and brain tumours.
The discoveries may in the long term also open new principles
for cancer therapy. Already now clinical trials are in progress
using inhibitors of CDK-molecules.
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