Biology Reference
In-Depth Information
BOX 14.2 Anaphase SwitchdCont'd
The steady state solution of Eq. (B2.1A) is B
d M AT
d t ¼
B T C 0
C 0 þ C T
k amb L $
X
M T
M AT
Þ
¼
B T C 0 /
(B2.4)
(C 0
k db /k dbc . The steady
state solution of Eq. (B2.1C) satisfies the quadratic equation
þ
C), where B T
¼
k sb /k db and C 0
¼
½ k imh H M AT
X Þþ k break
ð C T
X Þ$ X
¼ V production V removal
K diss X
þ k
ð
C T
X
Þ$ X
¼ð
M AT
X
Þ$ð
C T
Þ
(B2.2)
X
break
In Figure B2C we plot the two rate laws, V production and
V removal , as functions of M AT , for a representative set of
parameter values given in Table B2 . The points of intersection
of the two rate curves are steady state solutions of Eq. (B2.4) .
Clearly, the dynamical system may exhibit bistability, and in
Figure B2 D we indicate how the steady state values of M AT
depend on L, with all other parameters fixed at their values in
Table B2 . Notice that Mad2 remains active until 1 e L, the
fraction of aligned chromosomes, gets very close to 1, and
then Mad2 is abruptly inactivated as the last chromosome
aligns on the metaphase plate and the cell proceeds to
anaphase.
where K diss
k break /k assoc .
Solving this quadratic equation for X, we obtain
¼
k dissoc /k assoc and
k
¼
break
F ¼ M AT
þ C T
þ K diss þ K break C T
2M AT C T
X
¼
p
F 2
(B2.3)
F þ
4
ð
1
þ k break
Þ M AT C T
In Figure B2 B we plot X as a function of M AT , along with
C
C).
Substituting the results of the previous paragraph into
Eq. (B2.1B) , we obtain
¼
C T e X and B
¼
B T C 0 /(C 0
þ
inactivated by tyrosine phosphorylation of the Cdk subunit
( Figure 14.2 ). To enter mitosis, these phosphate groups
must be removed. The relevant phosphorylation and
dephosphorylation reactions are:
mammalian cells to block entry into S phase if DNA damage
is detected in G1. A surveillance mechanism upregulates
a master transcription factor, p53, which induces synthesis of
repair enzymes and of a CKI (p21 WAF1 ) that inhibits
CycE:Cdk2 and blocks cell cycle progression in late G1. If
the damage can be repaired, then the CKI is removed and the
cell can proceed into S phase, as usual. If the damage cannot
be repaired, then p53 induces synthesis of pro-apoptotic
proteins and the damaged cell commits suicide.
Similarly ( Figure 14.10 , right), the cell can create
a checkpoint in telophase (T), with partially degraded
CycB and incompletely released Cdc14, if the mitotic exit
pathway ( Figure 14.5 C) is compromised. This strategy is
employed by budding yeast cells to implement a 'spindle
alignment' checkpoint [59] . Budding yeast cells determine
the location of the cell division plane early in the cell
cycle, at the point of bud emergence [78] . At the end of the
cycle, the bud must separate from the mother cell at the
neck between the two. Cell division will be successful only
if the mitotic spindle is properly aligned with one pole in
the mother-half of the cell and the other pole in the
daughter-half. If this is the case, then, as the spindle
elongates in late anaphase and pushes one mass of chro-
mosomes into the bud, the spindle pole comes into contact
with the bud cortex. This physical proximity brings
together a G-protein (Tem1) and its GEF (Lte1), and the
activated form of Tem1 activates a kinase that provides
additional phosphorylation of Net1 and complete release
of Cdc14 [86] . If the spindle is not properly aligned, then
Tem1 does not become activated and Cdc14 is not fully
released. Cell cycle progression blocks in telophase to give
the cell time to reorient the spindle.
Reaction
Enzyme
Cdk1:CycB
P-Cdk1:CycB (less active);
Wee1
/
P-Cdk1:CycB
Cdk1:CycB (more active);
Cdc25-P
/
Wee1
Wee1-P (less active);
Cdk1:CycB
/
Wee1-P
Wee1 (more active);
CAP
/
Cdc25
Cdc25-P (more active);
Cdk1:CycB
/
Cdc25-P
/
Cdc25 (less active);
CAP
Clearly, Cdk1:CycB and Cdc25 are involved in a positive
feedback loop (mutual activation) [79,80] ,andCdk1:CycB
and Wee1 are involved in a double-negative feedback loop
(mutual antagonism) [81,82] . This network controlling the
G2/Mtransition is strongly bistable ( Box 14.3 ), as first pointed
out by Novak and Tyson [83] . The theoretical predictions of
that paper were confirmed 10 years later by two groups
independently and simultaneously [84,85] ( Figure 14.9 ).
ADDITIONAL CHECKPOINTS
It should be obvious now that additional checkpoints can be
created by realigning the curves in Figure 14.8 . For instance
( Figure 14.10 , left), the cell can create a new checkpoint in
late G1, with a high level e but low activity e of starter
kinase (CycE), by synthesizing a stoichiometric inhibitor
(CKI) of CycE:Cdk2. This is exactly the strategy used by
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