oncogene and tumor suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival...
TRANSCRIPT
![Page 1: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/1.jpg)
Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival
Baltazar D. Aguda
Seminar given at Indiana University-Purdue University at Indianapolis, 6 Oct 2006
Mathematical Biosciences InstituteOhio State [email protected]
![Page 2: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/2.jpg)
Oncogene Tumor Suppressor Gene
x
x
x
x x
xx
DOMINANT(oncogene)
RECESSIVE(TSG)
INTERMEDIATE
Normal Cell Abnormal Cell Transformed Cell
Ref: R Hesketh, 1997
cancer
![Page 3: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/3.jpg)
Oncogenes & TSGs associated with some human cancers
cervical carcinoma : P53, RB1, MYC, MYCN, HRAS
colorectal carcinoma : APC, MCC, DCC, P53, TGFBR2, KRAS2
breast carcinoma : MYB, MYC, cyclin D1, cyclin D3, EGFR, HER2, HRAS, HSTF1, INT2, YES1, P53, RB1, BRCA1
CML : BCR-ABL, MYC, NRAS, RB1, P53, ERG, TLS,HOXA9, NUP98, AML1, EAP, EVI1, MN1, TEL,MDS1
![Page 4: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/4.jpg)
Cellular processes involved?
Molecular pathways & networks
The positions of these oncogenes and TSGs in these networks represent key nodes whose perturbations are crucial to the stability & evolution of the cancer-relevant cellular processes.
{ set of oncogenes & TSGs }
Network stability analysis & control
![Page 5: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/5.jpg)
Cellular processes involved?
Molecular pathways & networks
{ set of oncogenes & TSGs }
Network stability analysis & control
Cell cycleApoptosisSignalingAngiogenesisMetastasisSenescenceEtc.
![Page 6: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/6.jpg)
Cellular processes involved?
Molecular pathways & networks
{ set of oncogenes & TSGs }
Network stability analysis & control
Pathway ontology (BIOPAX)DBs/KBs (e.g. BIND, Biocarta, GenMAPP, Reactome)
Proposal: Library of Pathway Modules (functional modules according to specific cellular processes; e.g. Biocarta)
Repository of Models: Biomodels Database: http://www.ebi.ac.uk/biomodels/ CellML model repository: http://www.cellml.org/examples/repository/index.html
![Page 7: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/7.jpg)
Cellular processes involved?
Molecular pathways & networks
{ set of oncogenes & TSGs }
Network stability analysis & control
Topological analysis of qNETs (qualitative networks)
Network modularization schemes [e.g. Aguda & Algar (2003) Cell Cycle 2: 538 ]
Model extraction algorithms
Network perturbation and control protocols
![Page 8: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/8.jpg)
Oncogenes & TSGs in G1-S Network
![Page 9: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/9.jpg)
The G1-S transition & Restriction Point
R
G1
G2
M
S
![Page 10: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/10.jpg)
Fig 7 of reference above
R
Ekholm SV, Zickert P, Reed SI, Zetterberg A. (2001) Mol Cell Biol 21: 3256.
G1
![Page 11: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/11.jpg)
pRB
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK, DHFR
Cdc25Ap27
G1-S regulatory network
![Page 12: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/12.jpg)
pRB
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
RB1
defective in all retinoblastomas & in some other cancers:
small cell-lung carcinomas non-small cell lung cancers bladder & pancreatic carcinomas human breast carcinoma human prostate carcinoma
![Page 13: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/13.jpg)
pRB
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
E2F1Lung carcinomasEtc.
![Page 14: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/14.jpg)
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
KIP1
Leukemia, variety of solid tumors
![Page 15: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/15.jpg)
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/CDK4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
D-cyclin genes CCND1, CCND2, CCND3
D1 over-expressed in some gastric, breast, and aesophageal cancers. Sarcomas, uterine and colorectal carcinomas, malignant melanoma.
![Page 16: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/16.jpg)
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/CDK4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
CDK4
Dominant oncogene: CDK4 mutation isresistant to inhibition by INK4A.
CDK4 and CDK6 over-expressed in some tumorcell lines and CDK4 is amplified in some tumors(50% glioblastomas).
![Page 17: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/17.jpg)
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/CDK4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
Myc
Small cell lung carcinoma, breast and cervical carcinomas, Ewing’s sarcoma, Burkitt’s lymphoma, neuroblastoma,retinoblastoma
![Page 18: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/18.jpg)
pRB
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK, DHFR
Cdc25Ap27
Switching associated with R point?
![Page 19: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/19.jpg)
Network Structure & Instability
qNET analysis
![Page 20: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/20.jpg)
mij 0 Xj activates Xi ( Xj Xi ) mij 0 Xj inhibits Xi ( Xj Xi )
qNET graphs from M
mij= [xi/ xj]o •
1-cycle mii
Cycle strength graph
2-cycle mijmji
3-cycle mijmjkmki
Xi
Xi Xj
•
••
Xi Xj
Xk
•
••
![Page 21: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/21.jpg)
det(λI-M) = n + 1n-1 + 2 n-2 + … + n-1 + n = 0
where 1 = i [-C1(i)] 2 = i,j [-C1(i)][-C1(j)] + jk [-C2(jk)]3 = 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)
… ...
eigenvalues are functions of cycles only
dx/dt = f(x)
d(x)/dt = M(x)
Hurwitz Determinants, = functions of Ck ‘s
![Page 22: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/22.jpg)
X1 X2
X3
sufficient instability conditions
[1] S > 0
[2] T < 0
[3] SD < T when T > 0
1-cycle S = m33
2-cycle D = m12 m21
3-cycle T = m21 m13 m32
![Page 23: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/23.jpg)
X Y X X X X X Y
X Y X Y X Y
X Y X X X Y
X Y X Y X Y
X Y X Y
YY
X X XYYY
Y X Y Y X Y Y Y
X YX Y
X Y X Y
X Y X Y
X Y X YX Y X Y
U
S
MS
U UMS MS
U U U U U US S
U U U U U U
U
UUU U U US S
? ? ?
X Y
X Y
X Y
X Y
X Y
Topologies
U = unstable
S = stable
MS = marginally stable
? = undecided
qNET
![Page 24: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/24.jpg)
(2006)
![Page 25: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/25.jpg)
Modeling the G1 Checkpoint
![Page 26: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/26.jpg)
pRB
ORC
Cdc6
MCMs
pre-RCCdc7
E2F
DP
Cdk2/Cyclin-E
Myc
Max
pRb
Cyclin-D/cdk4 Cyclin-A/cdk2
Cdk2/Cyclin-E
TK,DHFR
Cdc25Ap27
Model Subnetwork for the Initiation of S phase
![Page 27: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/27.jpg)
p27/CycE/CDK2
iCycE/CDK2aCycE/CDK2.
.
p27
.
....
aCdc25AiCdc25A
CDK2p27 Cdc25A
A SHARP SWITCH
![Page 28: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/28.jpg)
Unstable couplings between cycles
BD Aguda (1999) Oncogene 18: 2846.
CDK - Cdc25 couple
![Page 29: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/29.jpg)
X1Y1
1f
1r
Y2X2
2r
2f
[Y2]ss
E2
s
s
u
[ ]ss
E1
Y2
Y1
[Y2]ss
E1
0
0
0
mass-action kinetics in graphs shown;similar for Michaelis-Menten kinetics
ss
ss
Y1 & Y2 turned ‘on’ only if
E1*E2 > (k1r/k1f)*(k2r/k2f)
Transcritical Bifurcation in Positively Coupled Cycles
![Page 30: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/30.jpg)
BD Aguda & Y Tang (1999) Cell Prolif. 32: 321.
1 sustained2 t_off = 803 t_off = 504 t_off = 305 t_off = 296 t_off = 28
time
Cyclin D/CDK4
GFs
Simulation of CDK2 activation
![Page 31: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/31.jpg)
Fig 7 of reference above
R
Ekholm SV, Zickert P, Reed SI, Zetterberg A. (2001) Mol Cell Biol 21: 3256.
![Page 32: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/32.jpg)
G1 G2S M
p27 E/cdk2
cdc25A
R G2 check
target of checkpoint signaling: unstable network motifs
Wee1 B/cdk1
cdc25C
Aguda & Tang (1999) Cell Proliferation
Aguda (1999) PNASAguda (1999) Oncogene
![Page 33: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/33.jpg)
J. Bartek & J. Lukas (2001) Curr. Opin. Cell Bio. 13 : 738
Pre-RC
CDK2
Cyc E
DNA damage
DNA replication
Cdc25A
ATM ATR
Chk1,2Mdm2
ARF
p53
p21
Cdc25A degradation
DNA damage signaling in G1
![Page 34: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/34.jpg)
Signaling, Cell cycle & Apoptosis
![Page 35: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/35.jpg)
Oncogenes in G1 signaling
Aguda BD (2001) Chaos 11 : 269-276.
![Page 36: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/36.jpg)
die cycle
signal
die cycle
signal
die cycle
signal
die cycle
signal
I II III IV
CLASSIFICATION OF SIGNALING PATHWAYS
Modularization
![Page 37: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/37.jpg)
p27Cdc25A cycE/cdk2
E2F
Myc
Rb cycD/cdk4
Apoptosome
DISC
Exec. Caspases Apoptosis
ARFMdm2p53
Bax Bcl-2
S phase
Bad
details of Case I
![Page 38: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/38.jpg)
die cycle
signal
a
b
c
b’
modeling Case I
Aguda & Algar (2003) Cell Cycle 2: 538
module-module interactions
![Page 39: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/39.jpg)
apoptosis
cycling
quiescent
Craciun, Aguda & Friedman (2005) Mathematical Biosciences and Engineering 2: 473-485
ks
ksd2Strength of negative feedback
signal intensity
![Page 40: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/40.jpg)
p53 vs Akt
with K.B. (Dave) Wee, PhD student
Cell Survival and Death
![Page 41: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/41.jpg)
Apoptosome
DISC
Exec. Caspases
DNA damage
p53
APOPTOSIS MACHINERY
FasL, Bax, PUMA
Akt
Growth factors
Bad, Caspase9, FKHR
p53 vs Akt
![Page 42: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/42.jpg)
p53 Akt
Bhuvanesh et al. Genes & Dev (2002) 16
Experimental indications of antagonism between p53 & Akt
![Page 43: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/43.jpg)
Feedback loops between p53 & Akt
p53
AktPTEN
Mdm2
PIP3
Mayo, L. D. & Donner, D. B. (2002) Trends Biochem. Sci. 27, 462-467.
![Page 44: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/44.jpg)
p53
AktPTEN
Mdm2
PIP3
TP53
Mutated in about half of known human cancers.
![Page 45: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/45.jpg)
p53
AktPTEN
Mdm2
PIP3
PTEN
Cancers of the breast, prostate, liver,stomach; gliomas; etc.
![Page 46: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/46.jpg)
p53
AktPTEN
Mdm2
PIP3
Akt1
Cancers of the breast,pancreas, prostate;carious carcinomas
![Page 47: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/47.jpg)
p53
AktPTEN
Mdm2
PIP3
Mdm2
Overexpressed in morethan 40 different typesof malignancies, incl.solid tumors, sarcomas,and leukemias
![Page 48: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/48.jpg)
11
20
*][
]53[
vvdt
Aktd
vvdt
pd
*][][][
]53[])53[(
]53*][[
*])[(
*][
])53[1])([(
][
2
22
1
11
1
11
00
AktAktAkt
pkpj
pAktkv
Aktj
Aktkv
pAktj
Aktkv
kv
tot
d
where
p53 AKT
Model Q1
Akt*
![Page 49: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/49.jpg)
Bistable switch
ActiveAkt
Total Akt Protein Level
Activep53
Steady State Level
![Page 50: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/50.jpg)
Model Q2
Model Q3
p53
AKT
Mdm2
p53
AKT
PTEN
PIP3
Mdm2
Wee & Aguda (2006) Biophys J
Robustness of bistable switch
![Page 51: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/51.jpg)
Robustness
k2
k0
Tot Akt
Tot Akt
3ss
3ss
1ss
1ss
![Page 52: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/52.jpg)
Wee & Aguda (2006) Biophys J
p*
k* k*
p*
k*
p*
k*p*
k*
p*
Activep53
Total Akt Protein Level
Apoptotic thresholds
![Page 53: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/53.jpg)
Apoptotic thresholds (predictions)
Active
p53
Total Akt Protein Level
sets of initial conditions that lead to apoptosis
![Page 54: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/54.jpg)
Summary & Conclusions
1. Networks of oncogenes & TSGs in the G1-S cell cycle transitionand p53-Akt interaction were analyzed.
2. There are unstable network motifs associated with G1 and G2checkpoints which are targeted by signaling pathways to arrest or slow down the cell cycle. Oncogenes & TSGs are involved in these
motifs and signaling.
3. The positive feedback loop between Akt and p53 gives rise to a bistable switch that may govern a cell survival-death switch. Model
predictions were given on apoptotic thresholds.
4. Modularization of networks coordinating the cell cycle and apoptosiswere presented and analyzed.
5. qNET analysis is useful for network stability stability analysis & formodel building.
![Page 55: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/55.jpg)
ACKNOWLEDGEMENTS
Collaborators: Keng Boon (Dave) Wee PhD Student, National University of Singapore
Avner Friedman Mathematical Biosciences Institute Ohio State University, USA
Gheorghe Craciun University of Wisconsin-Madison, USA
![Page 56: Oncogene and Tumor Suppressor gene networks in cell cycle checkpoints, apoptosis & cell survival Baltazar D. Aguda Seminar given at Indiana University-Purdue](https://reader035.vdocuments.us/reader035/viewer/2022081603/5697bfb71a28abf838c9ebcd/html5/thumbnails/56.jpg)
END