Cell Nucleus Biogenesis, Structure and Function
389
cycle as it incorporates the dramatic struc-
tural changes that are required to generate
the daughter cells. Mitosis can only oc-
cur if the chromosomes within the mother
cell are Frst duplicated. This is the most
critical requirement of the proliferation
process and eukaryotes have developed
a number of quality control mechanisms
called
checkpoints
to ensure that growing
cells can only attempt mitosis once the
process of DNA duplication is complete.
Other mechanisms ensure that the ini-
tiation of replication is tightly regulated
so that chromosomes are replicated once,
and only once in each cycle. The process of
DNA synthesis takes place in the S-phase
(for synthesis phase) of the cell cycle. G1
and G2 are gap phases that separate the
distinct S- and M-phases. During these
phases – and also during S-phase – the cell
grows and so continuously assimilates and
accumulates the components that are re-
quired to generate two new cells at the end
of mitosis. It goes without saying that if
proliferating cells are to maintain the re-
quired structural characteristic, each cell
that forms during mitosis must double in
mass before the next mitosis takes place.
±or mammalian cells, a typical cell cycle
will be completed in about 24 h. Breaking
down as: G1 6 to 10 h; S 8 to 10 h; G2 3
to5h
;M1h
.Variationsincellcycleoccur
predominantly during G1. The major cues
for proliferation are driven by families of
cell cycle proteins called
cyclins
and cy-
clin dependent kinases (cdks or cdcs). The
critical step that commits a cell to prolif-
eration occurs late in G1, about 2 h prior
to the onset of S-phase. This position of
the cell cycle is referred to as ‘‘start’’ and
onceace
l
lpassesth
ispo
in
ti
tislocked
into a cycle of events that will inevitably
lead to the formation of the daughter cells.
A critical part of this transition involves
the phosphorylation of the tumor suppres-
sor protein Rb (retinoblastoma protein)
by a cyclinD/cdk4/6 and cyclinE/cdk2
complexes (±ig. 2). This Rb modiFcation
alters the association of Rb with a fam-
ily of transcription factors – E2±1–6 and
DP1–2 – that function to activate the ex-
pression of other genes involved in the
cell cycle progression and DNA replica-
tion, such as cdc2 and DNA polymerase 2.
The activity of the cyclin/cdk complexes is
driven by mitogenic cues and restrained by
the tumor suppressor proteins p21
cip
/
kip
and p16
INK4a
.
Cells with protracted cell cycle times
have extended pre-start periods. In addi-
tion to this, cells with proliferative potential
can ‘‘rest’’ in a G0 phase of the cycle. This
state is usually perceived as an extension
o
ftheG1pha
sewhe
rece
l
l
sa
reab
leto
respond to growth signals once the appro-
priate signaling cues are provided. Once
cells in this quiescent state are activated by
the requisite mitogens, it will usually take
15 to 20 h before the onset of S-phase. It
is also important to remember that most
cells have limited proliferative potential so
that after growing and dividing for some
time (perhaps 50-cell doubling would be
a typical duration) they assume a nonpro-
liferative state. Now cells will be destined
to perform the speciFc function that their
pattern of gene expression dictates. Such
cells become terminally differentiated and
are no longer capable of accessing the
cell cycle. A minority of cells in multi-
cellular organisms maintain a long-term
undifferentiated status. These special cells,
called
stem cells
, have a privileged status
that allows them to evade differentiation
and senescence.
2.3.1
Mitosis
Once a cell has performed DNA replica-
tion and has acquired the mass needed
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