cell cycle

1
( 30 June 2006 )
MBI Journal Club on Models of Cell-Fate Regulation
CELL CYCLE
Part Two
(contd)
2
(No Transcript)
3
Mammalian Cell Cycle
M
G1
G2
R
S
4
(No Transcript)
5
(No Transcript)
6
Ekholm SV, Zickert P, Reed SI,
Zetterberg A. (2001) Mol Cell Biol 21 3256-3265.
These kinetic data rule out the hypothesis that
passage through R is dependent on the
accumulation of cyclin E but suggest,
instead, the converse, that passage through R is
a prerequisite for cyclin E accumulation
R
Fig 7 of reference above
7
DNA damage
ATM
ATR
ARF
Chk1,2
Mdm2
Cyc E
Cdc25A degradation
p53
CDK2
Ub
Cdc25A
Cyc E
CDK2
Cyc E
CDK2
Pre-RC
DNA replication
J. Bartek J. Lukas (2001) Curr. Opin. Cell Bio.
13 738
8
GFs
Cyclin-D/cdk4
Cyclin-A/cdk2
p16, p27
pRb
pRB
Cdc6
Cdc45
E2F
ORC
DP
MCMs
Cdc7/Dbf4
Cdk2/Cyclin-E
Cdk2/Cyclin-E
Cdc25A
p27
Myc
Max
GFs
G1-S mammalian
9
eigenvalues are functions of cycles only
ln a1ln-1 a2 ln-2 an-1l
an 0 where a1 ?i -C1(i) a2
?i,j -C1(i)-C1(j) ?jk -C2(jk) a3
?i,j,k -C1(i)-C1(j)-C1(k) ?i,jk
-C1(i)-C2(jk) ?ijk -C3(ijk) ...
where C1(i) mii (1-cycles) C2(jk)
mjkmkj (2-cycles) C3(ijk) mijmjkmki
(3-cycles) ...
10
Model Subnetwork for the Initiation of S phase
Cyclin-D/cdk4
Cyclin-A/cdk2
TK, DHFR
pRb
pRB
Cdc6
E2F
ORC
DP
MCMs
pre-RC
Cdc7
Cdk2/Cyclin-E
Cdk2/Cyclin-E
Cdc25A
p27
Myc
Max
11
A SHARP SWITCH
p27/CycE/CDK2
.
.
.
iCycE/CDK2
p27
aCycE/CDK2
.
.
.
.
aCdc25A
iCdc25A
12
Unstable couplings between cycles
BD Aguda (1999) Oncogene 18 2846.
13
Transcritical Bifurcation in Positively Coupled
Cycles
0
0
ss
ss
mass-action kinetics in graphs shown similar for
Michaelis-Menten kinetics
0
14
(No Transcript)
15
p27/CycE/CDK2
CycD/CDK4/p27
.
.
.
.
.
.
iCycE/CDK2
p27
aCycE/CDK2
CycD/CDK4
.
.
.
.
Cdc25A
.
pRB-P
.
pRB/E2F
E2F
pRB
Kinetic Model
16
p27/CycE/CDK2
CycD/CDK4/p27
.
.
.
.
.
iCycE/CDK2
p27
aCycE/CDK2
CycD/CDK4
.
.
.
.
aCdc25A
iCdc25A
c-Myc
E2F
Coupled PD cycles between Cdc25A and CDK2
17
Simulation of CDK2 activation
1 sustained 2 t_off 80 3 t_off 50 4
t_off 30 5 t_off 29 6 t_off 28
time
GFs
Cyclin D/CDK4
BD Aguda Y Tang (1999) Cell Prolif. 32 321.
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
Aguda, PNAS 96 11352(1999)
22
Signaling, Cell Cycle Apoptosis
23
(No Transcript)
24
CLASSIFICATION OF SIGNALING PATHWAYS
signal
signal
signal
signal
die
cycle
die
cycle
die
cycle
die
cycle
I
II
III
IV
25
details of Case I
Myc
E2F
Rb
cycD/cdk4
p53
Mdm2
ARF
Bax
Bcl-2
Bad
p27
Cdc25A
cycE/cdk2
DISC
S phase
Apoptosome
Exec. Caspases
Apoptosis
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
(No Transcript)