Healthcare and Medicine Reference
In-Depth Information
The core of the cell-cycle control machine are the cyclin-
dependent kinases (Cdk) and their regulatory subunits, the
cyclins. The cyclins were originally discovered as proteins
that change dramatically in their levels of expression during
the stages of the cell cycle. The transcription, translation,
and destruction of each of these proteins are tightly tied to a
particular stage of the cell cycle. The figure shows the period
in the cell cycle when each of the cyclins is expressed.
The cyclins form complexes with specific CDKs,
thereby activating the CDK to phosphorylate substrate
proteins and consequently drive the cell through the next
stage of the cycle. The best characterized of the
cyclin/CDK pairs is that of cyclinB and CDK2, which
control the passage of the cell through the M-phase of the
cycle. In the late 1980s it was found that a cell-free extract of
proteins could cause a cell to progress through the M-phase
of the cell cycle. This activity was called MPF, for mitosis
promoting factor. CyclinB and cdk2 were discovered to be
the active components of this activity. This complex of two
proteins is a key regulator of this transition. Since that time
there has been a considerable amount of study of these pro-
teins and the other cyclins and their paired Cdk.
Other proteins regulate the cyclin/CDK activity as
well. For a CDK to be activated it must be phosphorylated
at a particular threonine residue, 161, and at the same
time be dephosphorylated on residues threonine 14 and
tyrosine 15. The proteins that effect these phosphorylation
events are therefore important regulators of the CDK
activity in a cell. These regulatory proteins include CAKs
(CDK-activating kinases) and phosphatases (like string).
In addition, there are a number of CDK inhibitors, small
proteins that act to inhibit CDK activity by binding to
them and blocking their catalytic activity. The INK group,
p15 , p16 , p18 , and p19 , all interact with CDK4 and 6 , the
CDK important in the transition from G1 to S-phase. A
second class of these proteins includes p21 , p27 , and p57
and can bind to and inhibit all known CDKs.
A particularly important cell-cycle transition is the
entry in to the S-phase, which is the first step in the
mitotic cycle. One of the most important regulators of this
step is the cyclinD complex with either CDK4 or CDK6 .
When a cell receives a stimulus to enter the cycle, cyclinD
is increased in its expression (see below) and forms a
complex with CDK4/6 . When this complex is phosphory-
lated by CAK, it can catalyze the phosphorylation of
several key substrate proteins necessary for the S-phase
of the cycle. One of the most important of these is called
the retinoblastoma protein, or Rb, which was originally
identified as linked to a childhood retinal tumor. This
protein is also one of a family of genes, known collectively
as the pocket proteins, that act as tumor inhibitors; when
they are absent or inactivated by a mutation, cells
undergo unrestricted proliferation. In G1 the Rb protein
is unphosphorylated, and this keeps the cell from enter-
ing the S-phase; when the cyclinD /CDK complex phos-
phorylates this protein, the cell can then express the
proteins necessary to move into the S-phase.
The cell-cycle control machine shown in the figure is a
highly coordinated complex sequence of protein interac-
tions. For the most part, once the sequence is set in motion,
it proceeds in an autonomous manner. However, there are
a few points where extracellular signals can regulate the
progression from one phase of the cycle to another. In
mammalian cells, the major checkpoint is in the transition
from the G1 phase of the cycle to the S-phase. This was first
discovered by inducing tissue-cultured cells to cease their
mitotic activity by withdrawing critical serum compo-
nents from their medium. By adding back the serum for
brief periods, it was found that once the cycle was started
again, the serum was not needed, until after the cell had
completed an entire cycle. In general, it is thought that
when growth factors regulate cellular proliferation, they
do so by acting at the G1 to S transition, either by promot-
ing cyclinD expression/activity to stimulate entry into the
next cycle, or alternatively by increasing the expression of
a cyclin inhibitor, like p27 , to block entry into the next cycle.
In Drosophila cells, the G2 progression is also frequently the
target of control. Cells in the developing eye imaginal disc
are held in G2 until they receive an extracellular signal,
hedgehog, to trigger their progression through the M-phase.
Cyclin B
Cyclin A
Cyclin D
Cyclin E
Cyclin A
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