world cancer report - iarc

WAF1/CIP1
WAF1/CIP1
Through this mechanism, E2Fs exert a
dual function both as transcriptional
repressors in G1, when bound to pRb, and
as transcriptional activators in G1/S and
in S phase, after dissociation of pRb from
the complex. Recent observations suggest
that transcriptional repression by E2Fs is
essential to prevent the premature activation
of cell cycle effectors, which would
scramble the temporal sequence of
molecular events and preclude cell cycle
progression.
Cell cycle checkpoints
The notion of “cell cycle checkpoints” is
also derived from early studies in Xenopus
oocytes and in yeast mutants. In S. cerevisiae,
commitment to the mitotic cycle
requires the crossing of a “restriction
point” called the start transition. Failure to
cross this transition results in cells being
blocked in the G1 phase of the cycle.
Another control point has been clearly
identified after S phase, at the transition
between G2 and M phases. Cells unable to
cross this checkpoint may remain blocked
in a pre-mitotic, tetraploid state.
Physiologically, this checkpoint is active in
106 Mechanisms of tumour development
WAF1/CIP1
Fig. 3.27 The progression of the cell cycle depends upon the sequential activation and inactivation of
cyclin/CDK complexes. This process requires the synthesis of cyclins, the formation of a complex
between a specific cyclin and a CDK, and modification of the CDK to convert this enzyme to an active
form. The enzyme’s activity may be disrupted by a specific inhibitor, a CDKI.
KIP1
KIP2
WAF1/CIP1
CDK2A
CDK2B
INK4D
WAF1/CIP1
KIP1
KIP2
germ cells during the second division of
meiosis: cells that have undergone the
first, asymmetric division of the meiotic
cycle arrest in G2 until completing the second
division, which is triggered by fertilization.
This concept of “cell cycle checkpoints”
was later extended to all mammalian
cells [5]. It is now common to envisage
the mammalian cell cycle as a succession
of checkpoints that have to be negotiated
in order for division to be achieved.
There is no clear agreement on how many
such checkpoints exist in the mammalian
cell cycle, or on their exact position.
Control of cdk1 at G2/M transition
The regulation of the complex between
cdk1 (also called p34cdc2) and cyclin B
exemplifies how different factors co-operate
to control the activation of
cyclin/CDK complexes at a cell cycle
checkpoint. This activation process
requires co-operation between three levels
of regulation: association between the
two partners of the complex, post-translational
modifications of the kinase and of
the cyclin, and escape from the negative
regulation exerted by the CDKIs.
In early G2, cdk1 is in an inactive form.
Its activation requires first association
with cyclin B, followed by post-translational
modification of the kinase itself.
This modification includes phosphorylation
of a conserved threonine residue
(Thr161) by a kinase complex called CAK
(CDK-activating kinase), as well as
dephosphorylation of two residues localized
within the active site of the enzyme,
a threonine (Thr14) and a tyrosine
(Tyr15). The removal of these phosphate
groups is carried out by the dual-specificity
phosphatases of the cdc25 group,
comprising three isoforms in humans (A,
B and C). Activation of these phosphatases
is therefore crucial for the activation
of cyclin B/cdk1 complexes. The
phosphatase is directly controlled by a
number of regulators, including plk1
(polo-like kinase), an activating kinase,
pp2A, (protein phosphatase 2A), an
inhibitory phosphatase and 14-3-3s, a
signal transduction molecule which complexes
with cdc25, sequesters it in the
cytoplasm and thus prevents it from
dephosphorylating its nuclear targets. Of
course, the action of cdc25 phosphatases
is counteracted by kinases that
restore the phosphorylation of Thr14 and
Tyr15, named wee1 and mik1 [6].
Following the activation process outlined
above, the cyclin B/cdk1 complex
is potentially able to catalyse transfer of
phosphates to substrate proteins.
However, in order to achieve this, it has
to escape the control exerted by CDKIs,
such as p21. The function of this CDKI is
itself controlled by several activators,
including BRCA1, the product of a breast
cancer susceptibility gene (Oncogenes
and tumour suppressor genes, p96). The
p21 protein is removed from the complex
by a still poorly understood phosphorylation
process, which also drives
rapid degradation of the protein by the
proteasome. This leaves the cyclin
B/cdk1 complex ready to function, after
a final step of autophosphorylation, in
which cdk1 phosphorylates cyclin B. The
complex is now fully active and ready to
phosphorylate many different substrates,
such as nuclear lamins, during
entry into mitosis.