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MECCANISMI DELLACANCEROGENESI
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Pancreatic Skin Breast
BrainLung Prostate
Leukemia Hodgkins Non-Hodgkins
SOLID
CANCERS
LIQUIDCANCERS
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5
0
10
15
20
25
30
35
10
10
10
10
10
10
10
10
10
10
10
10
0
1
2
3
4
5
6
7
8
9
10
11
10
10
10
10
10
10
10
10
10
10
10
10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
Divisioni
cellulari
No. Di
cellule
Peso
(g) Ambiente estile di vita
PREVENZIONEPRIMARIA
Organismo
ospite (chemio -prevenzione)
PREVENZIONESECONDARIA
TERAPIA,RIABILITAZIONE e
PREVENZIONETERZIARIA
TUMORE BENIGNO
INIZIAZIONE(giorni - settimane)
PROMOZIONE(anni - decenni)
CANCRO
PROGRESSIONE(~ 1 anno)
INVASIONE
Dose espositiva
Dose farmacologica
Dose cellulare
Dose bersaglio
Dose molecolare
TOSSICOCINETICAE METABOLISMO
DANNO E RIPARODEL DNA
METASTASI
CRESCITA DELLAMASSA NEOPLASTICA
PROCESSO DICANCEROGENESI
STRATEGIE DIINTERVENTO
12
40 10
310 MASSA NEOPLASTICA
CHEM
IOPREV
ENZIO
NE
S. De Flora et al., Mutat. Res. 480481, 922, 2001
Multistadi / field cancerization
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Controlli
NACDMBADMBA + NAC
8-oxo-dG/105 nucleotidi
.0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5
ControlliNACDMBADMBA + NAC
Addotti al DNA/108 nucleotidi
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
Controlli / DMBAEspressione diCx43
Cellule M13SV1 Cellule M13SV1R2 Cellule M13SV1R2N1
CELLULE EPITELIALI MAMMARIE UMANEDI ORIGINE STAMINALE
ControlliNACDMBADMBA + NAC
Celluleapoptotiche (%)
0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10
Differenze significative
DMBA vs. controlliS. De Flora et al., Int. J. Oncol., 29, 521529, 2006
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Controlli
NACDMBADMBA + NAC
8-oxo-dG/105 nucleotidi
.0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5
ControlliNACDMBADMBA + NAC
Addotti al DNA/108 nucleotidi
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
Controlli / DMBAEspressione diCx43
Cellule M13SV1 Cellule M13SV1R2 Cellule M13SV1R2N1
ControlliNACDMBADMBA + NAC
Celluleapoptotiche (%)
0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10
Differenze significative
DMBA vs. controlliS. De Flora et al., Int. J. Oncol., 29, 521529, 2006
CELLULE EPITELIALI MAMMARIE UMANEDI ORIGINE STAMINALE
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INIZIAZIONE DEL CANCRO
Tossicocinetica e metabolismo
Danno genotossico
Riparazione del DNA
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METABOLISMO DEGLI XENOBIOTICI
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ATTIVITA METABOLICHE DI FASE I E DI FASE IIE LORO POLIMORFISMI GENETICI
Drug-metabolizing enzymes known to exhibit common polymorphisms at thegenomic level that have been associated with changes in drug effects; however,almost every gene involved in the drug metabolism is subject to commongenetic polymorphisms that may contribute to interindividual variability in drugresponse and drug toxicity.
Phase I Phase II
DPD
NQO1
Epoxidehydroxylase
others
CYP1A1/2CYP1B1
CYP2A6
CYP2B6CYP2C8
CYP2C9
CYP2C19
CYP2O6
CYP2E1
ADHALDH
CYP3A4/5/7
others
NAT1
NAT2
GST-M
GST-TGST-P
GST-A
UGTSSTS
HMT
COWTTPWT
oxidases
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OO
O
HO
OH
HO
OH OH
OH
OH
HO
O
HO
OH
O
9,10Diol7,8oxide 7,8Diol9,10oxide
9,10Dihydrodiol 7,8Dihydrodiol
Mono-oxygenase
Epoxide hydratase
4,5Dihydrodiol
9,10Oxide 7,8Oxide 4,5Oxide
Mono- oxygenase
Benzo[a]pyrene K region
Bay region1
2
3
4
567
8
9
10
11
12
Phenols and quinones
Simple epoxides
Dihydrodiols
Diol- epoxides
Attivazione metabolica del benzo[a]pirene
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GLUCOSE
G6P G6PD 6PG 6PGD
NADPH
NADP + H+
GSSG
REDUCTASE
GSSG
2 GSH
GSH
PEROXIDASE
2H2O
H2
O2
GLUCOSO
G6P G6PD 6PG 6PGD
NADPH
GSSG
REDUTTASI
GSSG
2 GSH
GSH
PEROSSIDASI
2H2O
H2O2NADP + H+
CICLO DEL GLUTATIONE
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GSH = Glutatione ridotto
GST = Glutatione S-trasferasi
GSTM1
GSTT1
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GSTM1 GENOTYPE STATUS AND DNA ADDUCT LEVELSIN SMC OF HUMAN ATHEROSCLEROTIC LESIONS
*P< 0.05, **P< 0.01 A. Izzotti et al., FASEB J. 15, 752-757, 2001
32P postlabelledDNA adducts
GSTM1+(n = 36)
GSTM1(n = 39)
Ratio(/+)
Spot 1Spot 2Spot 3
Spot 4Spot 5Spot 6Spot 7Spot 8Spot 9DRZ
Total
0.460.110.23
0.100.130.260.360.250.64
10.8013.80
0.630.250.49
0.180.350.270.480.351.076.169.77
0.580.200.51
0.280.280.460.860.772.74
16.4122.67
0.740.280.74*
0.430.57**0.521.23*1.40**5.97**10.63**18.63**
1.31.82.2
2.82.21.82.43.14.31.51.6
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METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978
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METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978
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CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELLPOPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM
De Flora et al., Carcinogenesis 18, 531537, 1997
PORTAL SYSTEM BLOOD[187 - 234 mg Cr(VI)]
INTESTINAL BACTERIA[11 24 mg Cr(VI) eliminateddaily with bacteria in feces]
GASTRIC JUICE[> 84 88 mg Cr(VI)/day]
SALIVA [0.7 2.1 mg Cr(VI)/day]
LIVER CELLS[3,300 mg Cr(VI)]
BRONCHIALTREE CELLS
PERIPHERALLUNG PARENCHYMACELLS [260 mg Cr(VI)]
ELF [0.9 1.8 mg Cr(VI)]
PAM [136 mg Cr(VI)]
BLOOD[187 234 mg Cr(VI)]
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BENIGN TUMOR
INITIATION(days - weeks)
PROMOTION(years - decades)
CANCER
PROGRESSION(~ 1 year)
INVASION
Exposure dose
Pharmacologic dose
Cellular dose
Target dose
Molecular dose
TOXICOKINETIKSAND METABOLISM
DNA DAMAGE
AND REPAIR
CARCINOGENESISPROCESS
NEOPLASTIC MASS
METASTASIS
THRESHOLDS IN CARCINOGENESIS?
DNA repairDNA repair ApoptosisApoptosis
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INIZIAZIONE DEL CANCRO
Tossicocinetica e metabolismo
Danno genotossico
Riparazione del DNA
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CARIOTIPO UMANO
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C
NC
GNGAmes reversion test
Accuracy = 74.7% (68/91)
23.2%(16/69)
Sensitivity
76.8%(53/69)
31.8%(7/22)78.2%(15/22)
Specificity
C
NC
GNGDNA-repair test
Accuracy = 73.7% (59/80)
20.7%(12/58)
Sensitivity79.3%(46/58)
40.9%(9/22)59.1%
(13/22)Specificity
CORRELAZIONE FRA
MUTAGENICITA ECANCEROGENICITA
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EFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMOEFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMO
Morte cellulare (apoptosi)
Tumori e altre malattie cronico-degenerative
Invecchiamento e patologia associata
MUTAZIONI IN CELLULE SOMATICHE(in et adulta o in epoca embrionale)
MUTAZIONI IN CELLULE SOMATICHE(in et adulta o in epoca embrionale)
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EFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMOEFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMO
Sterilit, aborto, morte perinatale(mutazioni dominanti letali)
MUTAZIONI IN CELLULE GERMINALIMUTAZIONI IN CELLULE GERMINALI
Malattie genetiche nei neonati(mutazioni dominanti non letali)
Malattie genetiche in generazioni successive(mutazioni recessive)
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mtDNA
AGEING
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R. Balansky et al., Cancer Res. 56, 1642-1647, 1996
NAC
NAC +
mtDNA
nDNA
ADDOTTI AL DNA POLMONARE IN RATTI ESPOSTI AFUMO DI SIGARETTA
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INIZIAZIONE DEL CANCRO
Tossicocinetica e metabolismo
Danno genotossico
Riparazione del DNA
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XP
AT
AF
Suscettibilit individuale
RIPARAZIONEDEL DNA
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Mechanisms
XPC
hHR
23B
33
55
TF
IIH
G1G1
SS
G2G2
MM
Cell
Cy
cle
Cell
Cy
cle
p21
Chk2
PNK
DNA-PKcs
RNAPol
Rad1
XAB2
X
P
B
TFIIH
XPG
ERC
C1
XPF
NERNER
Cross-
LinkingC
ross-
Linkin
g
Ku70/80Ku70
/80
XRCC4Li
gIV
Rad50
PARP
UV LightUV Light
BRCA1
SSBreakbyX-Rays
S
SBreakbyX-Rays
DNA-DamageCheckpoint
DNA-DamageCheckpoint
p53Degrada
tion
p53Degrada
tion
UbU
b Ub
Ub
Rad51
Rad51
BARD1
IG
F1
BRC
A1
DSB
DSB
P PP
P
JNK/SAPK
DSB
DSB
Ligase
PCNA
PCNA
PCNA
NBS1 MR
E11
Pol-
/
FEN1 Po
l-
NHEJNHEJ
ApoptosisApoptosis
Cell ProliferationCell Proliferation
GADD
45
MGMT
DNAPol
Oxygen RadicalsAlkylating Agents
Spontaneous Reactions
Oxygen RadicalsAlkylating Agents
Spontaneous Reactions
MMRMMR
BERBER
Deacetylatio
n &Demethy
lationof
GuanineDeace
tylation &De
methylation
of
Guanine
NucleusNucleus
BE
R
BE
R
MMRMMR
BERBER
BERBER
SS-Break
s
byX-Ray
sSS-Break
s
byX-Ray
s
Repair
Repair
Depurination& Deamination
Depurination& Deamination
DNA-
Dam
age
Chec
kpoin
t
DNA-
D
am
ag
e
Chec
kpoin
t
Endogenous Agents(Water & ROS)
Endogenous Agents
(Water & ROS) ReplicationErrors(DNAPol&IDLs)
ReplicationErrors(DNAPol&IDLs)
UU
33
55
GGOx
oOx
oRF
-PLo
ads
RF-P
Load
s
PCNA
onto
DNA
PCNA
onto
DNA
Homo
logou
sReco
mbina
tion
Homo
logou
sReco
mbina
tion
ProofReading
ProofReadingIRDa
mageIRDamage
hN
TH
TRE
X1
UNG2
TRE
X2
MutS MutSMSH2
MSH3
MS
H2 MutS MutS
Smoki
ngSmoki
ng
OHOHPP
X-Rays &Anti-Tumor Agents
X-Rays &Anti-Tumor Agents
AbasicSite
AbasicSite
NERNER
p53
MDM2
Recom
binatio
nal
Repair
Recom
binatio
nal
Repair
FANCs
Po
l-SNM1
Estrogen
Estrogen
R
PA
XPD Rad
24Rad17
Mec1
CSA
Trans
cripti
on
Coupl
ed-
NER
Trans
cripti
on
Coupl
ed-
NER
ATMAT
R
Chk1
p53
UV Light Ionizing Radiation, BulkyAdducts& ROS
UV Light Ionizing Radiation, BulkyAdducts& ROS
Proteasome
XRCC1
BRCA1
UV & BulkyAdducts
UV & BulkyAdducts
X
P
A
C
S
B
Rad9
BRCA2
Hu
s1
Rad9
LigIII
hOGG1
GGMeMe
M S H 6
MBD4
SMUG1
AP
E1
Rad52
2009ProteinLounge.com
2009ProteinLounge.com
C
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PROMOZIONE DEI TUMORI
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PROMOZIONE DEL CANCRO
Promotori fisici / meccanici
Promotori biologici
Promotori chimici
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PROMOZIONE DEL CANCRO
Promotori fisici / meccanici
Promotori biologici
Promotori chimici
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SPECIE REATTIVE DELLOSSIGENO
O2
H2O
e
e
e
e
OSSIGENO MOLECOLARE
O2 ANIONE SUPEROSSIDO
H2O2 IDROGENO PEROSSIDO
OHRADICALE IDROSSILE
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SPECIE REATTIVE DELLOSSIGENO
O2Lucecoloranti
OSSIGENO MOLECOLARE
O2 OSSIGENO SINGOLETTO
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PROMOZIONE DEL CANCRO
Promotori fisici / meccanici
Promotori biologici
Promotori chimici
ORGANOSPECIFICITA DEI PROMOTORI
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ORGANOSPECIFICITA DEI PROMOTORI
NaCl Stomaco
Saccarina Vescica
Componenti della bile Colon
Estrogeni Mammella
Fenobarbital Fegato
Componenti del fumo Polmone
TPA Cute
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5
0
10
15
20
25
30
35
10
10
10
10
10
10
10
10
10
10
10
10
0
1
2
3
4
5
6
7
8
9
10
11
10
10
10
10
10
10
10
10
10
10
10
10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
Divisionicellulari
No. Dicellule
Peso(g) Ambiente e
stile di vita
PREVENZIONEPRIMARIA
Organismo
ospite (chemio -prevenzione)
PREVENZIONESECONDARIA
TERAPIA ePREVENZIONE
TERZIARIA
TUMORE BENIGNO
INIZIAZIONE(giorni - settimane)
PROMOZIONE(anni - decenni)
CANCRO
PROGRESSIONE(~ 1 anno)
INVASIONE
Dose espositiva
Dose farmacologica
Dose cellulare
Dose bersaglio
Dose molecolare
TOSSICOCINETICAE METABOLISMO
DANNO E RIPARO
DEL DNA
METASTASI
CRESCITA DELLAMASSA NEOPLASTICA
PROCESSO DICANCEROGENESI
STRATEGIE DIINTERVENTO
12
40 103
10MASSA NEOPLASTICA
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ANGIOGENESI E
ANTIANGIOGENESI
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ANGIOGENESI E LINFANGIOGENESI
GENI IMPLICATI IN LINFANGIOGENESI (K. Alitalo et al., Nature, 2006)
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Pathway
VEGFA,VEGFC,VEGFD
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VEGF
R2
PLC
PIP3
PIP2PI3K P
P PIP2
P
p38
MKK3/6
FAK
Paxillin
SHC
GRB2SOS
Pathway
P
P
P
BAD
P
Caspase9
HSP90
eNOS
MAPKAPK2/3MAPKAPK2/3
ActinReorganization
ActinReorganization
DAG
MEK1/2
Ras
IP3
VEGFD
Sck
VRAP
HSP27
ERK1/2
PKC
Raf1
Ca2+
cPLA
Endo
thelial
Cell
Endo
thelialC
ell
Focal Adhesion
Turnover
ProstaglandinProduction
Vascular CellPermeability
Gene Expression & CellProliferation
ANGIOGENESIS
Cell Survival
Nitric Oxide
Production
Src
Akt/PKB
CellMigration
2009ProteinLounge.com
2009ProteinLounge.com
C
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REGOLAZIONE GENETICA DELLA
PROLIFERAZIONE CELLULARE
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IL CICLOCELLULARE
ReplicativeReplicative
Cyclins and Cell Cycle
Regulation
Cyclins and Cell Cycle
Regulation
2009ProteinLounge com
2009ProteinLounge com
C
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P
P
PP
CDK1
CDK1
CDK1
CDK1
Cyclin-A
Ub
Rb
PP
P
PP
P
P
P
P
PPP
PRb
PP P
P
P
ATR
P P
E2FDP1
DP1
E2F
P
Rb
Rb
CDC25A
P
UbUb
UbiquitinationUbiquitination
UbiquitinationUbiquitination
Cyclin-H
CDC25A
E2F
Rb
Cyclin-
B
Cyclin-A
CDC25A
P
Wee1
MYT1
p21
E2F
Rb
Wee1
PP2A
Raf1
CDC2
5A
p21
P
Cyclin-A
Wee1p21
Wee1
TGF
p19(INK4D)
MYT1
Cyclin-D/D1
Cyclin-E
p18(INK4C)
p16(INK4A)p15(INK4B)
GSK3 p27(KIP1)
Cell CycleProgression
Cell CycleProgression
NucleusNucleus
S-Phase Genes[Cyclin-A, E,E2F, CDC2]
S-Phase Genes[Cyclin-A, E,E2F, CDC2]
ReplicativeScenescece
ReplicativeScenescece
ContactInhibition
ContactInhibition
MM
G2G2
ReplicativeSenescence
pSenescence
GrowthF
actor
Withd
rawal
Growth
Facto
r
Withd
rawal
C
IP/KIPFamily
CIP/KIPFamily
OffOff
OnOn
G1G1
RegulationRegulation
DNADamage
DNADamage
CDK4/6
ATM
p27(KIP1)
CDK7
Cyclin-H
CDK2CDK2
Cyclin-A
CDK2
CDK2
p27(KIP1)
p27(KIP1)Degradation
p27(KIP1)Degradation
SCFSCF
HDACs
p53
ProteinLounge.comProteinLounge.com
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PROTOONCOGENI
ONCOGENI
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TRASLOCAZIONE CROMOSOMICA
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MUTAZIONI PUNTIFORMI
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AMPLIFICAZIONE GENICA
GENI ONCOSOPPRESSORI
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GENI ONCOSOPPRESSORI
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Sindrome di Li-Fraumeni
Sindrome di von Hippel-Lindau
ChemotherapyChemotherapyIonizing
Radiation
IonizingRadiationHypoxiaHypoxia p53 SignalingUVUV
D
F
a
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p38
HIF1
Ub
Ub
14-3-3
MDM2
P P
P
P
E2F
c-FosP
Rb
P
P
BRCA1
AngiogenesisInhibition
AngiogenesisInhibitionCell Cycle
Progression
Cell CycleProgression
Gene ExpressionGene Expression
Cell SurvivalCell Survival
DNA DamageDNA Damage
Hypoxia InducedHIF1 Expression
Hypoxia InducedHIF1 Expression
ApoptosisApoptosis
p53Degradation
p53Degradation
DNA RepairDNA Repair
Ac
AcCAK
MDM2
PIAS1
JNK
Caspase
BCL2
BAI1
TSP1
GADD45
RbCDK2
CyclinD1
CDK4
CyclinE E2F
PCAF
DNA-PK
PTEN
ATM
p53
Akt
p53
p53
Ub
ATR
Sirt
HDAC
c-Abl
p53PML
p21CIP
PTEN
ProteasomeProteasome
HIPK2 CSNK1
p53
GSK3
Bax
D
R
5
a
s
Ac
p53
p300
Chk2
Chk1
2009ProteinLounge.com
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LOSS OF FHIT EXPRESSION IN SPRAGUE-DAWLEYFHIT
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Bronchialepithelium
Kidneytubular
epithelium
SHAM
1.4 0.74%
1.1 0.64%
RATS EXPOSED TO CIGARETTE SMOKE FOR 28 DAYS
ECS
4.9 1.96%P < 0.001 compared to SHAM
1.4 0.52%
ECS + NAC
3.1 1.7%P < 0.05 compared to ECS
1.3 0.71%
F. DAgostini et al., Cancer Res. 66, 393641, 2006
TUMORI DELLA MAMMELLA O DELLOVAIO
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U O O O O
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Colorectal carcinogenesis: adenomacarcinoma sequence. (Adapted from Kelloff GJ, Hawk ET,Crowell J, et al: Oncology 10(10):147184, 1996 and Ilyas M, Straub J, Tomlinson IP, et al: Eur J Cancer35:33551, 1999 and reprinted with permission (131, 132).
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