@derka

1

An explanation should be as simple as possible but not a bit simpler…

Albert Einstein

2

EGF

IGF

NGF

HGF

Erythropoietin

Estrogen

Testosterone

VEGF

5

G0

G1 checking point

S phase

G2-checking point

To be or not to be…an intracellular drama A computo-novella

Mitosis

Functional significance of genes in melanoma

DNA break

hMutShMSH2hMSH6}

hMIH1hPMS2

hMutL}

MMR (Mismatch Repair Mechanisms)

ATM

BRCA1

P

P

BRCA2 RAD51

BRCA1 RAD52 Repair

Gene for repair ofdouble strand breaks

Apoptosis

p53

+

p21

DeVita p.20056th Edition

Cyclin dependentKinase (cdk2)

Cyclin E}

RB E2F

RBP

E2F

Cell cycleactivation

Cycle arrest2

+

p16Cyclin dependentKinase (cdk4/6)

Cyclin D

}

MLH1PMS1PMS2

p27

TGF- NEJM 342:1350,2000

INK4 familyINK4 family

p15

p18

p19

cip/kip family

p57

Growthfactors

Growth receptors mediated growth stimulation

EGF receptor

EGF

TK TK

Grb2adapter

p21 rasinactive

MAP kinases

jun

+ P

fos

+ P

jun fos

P P

myc Cyclin D

TK=Thyrosine kinase

3

p21 rasactive

AKT

Proliferationsignals

Glucosemetabolism

Energy

Protein synthesis

Anti-apoptosis

Enhanced angiogenesis

PTEN

-

MAP = Mitogen activated protein kinase

P

SH2

GEF

GEF = Guanine exchange factor

GDP GTP

GAP

GAP= GTPase activating protein

Apoptosis mechanismsApoptosis mechanisms

Mitochondria

BCL-2

Bax Bid

Cytochrome C AIF

Cytochrome C AIF

Caspases

Apoptosis

18

BadBik

P53

+

CathepsinD

TNF

FAS

Ceramide

Apoptosis

EGF receptor

EGF

TK

TK=Thyrosine kinase

6

Enhanced angiogenesis

Proliferationsignals

MAP kinases

MAP = Mitogen activated protein kinase

Grb2adapter

P

GEF

GEF = Guanine exchange factor

p21 rasinactive

GDP

p21 rasactive

GTP

GAP

GAP= GTPase activating protein

Anti-apoptosis

Glucosemetabolism Energy

Protein synthesis

Ribosomebiosynthesis

jun

+ P

fos

+ P

jun fos

P P

myc

Erbitux

IressaHerceptin

Antiangiogenic factors

Cyclin D

Cell proliferation

Akt/PKB

Akt/PKB=Protein kinase B

EGF-R

2

Aktras

MAPK

Her2

Normal cell

EGF50 000

1 000 0001:20

9

Functional significance of genes in melanoma

DNA break

hMutShMSH2hMSH6}

hMIH1hPMS2

hMutL}

MMR (Mismatch Repair Mechanisms)

ATM

BRCA1

P

P

BRCA2 RAD51

BRCA1 RAD52 Repair

Gene for repair ofdouble strand breaks

Apoptosis

p53

+

p21

DeVita p.20056th Edition

Cyclin dependentKinase (cdk2)

Cyclin E}

RB E2F

RBP

E2F

Cell cycleactivation

Cycle arrest2

+

p16Cyclin dependentKinase (cdk4/6)

Cyclin D

}

MLH1PMS1PMS2

p27

TGF- NEJM 342:1350,2000

INK4 familyINK4 family

p15

p18

p19

cip/kip family

p57

G0

G1 checking point

S phase

G2-checking point

To be or not to be…an intracellular drama

Growthfactors

A computo-novella

Mitosis

Growth receptors mediated growth stimulation

EGF receptor

EGF

TK TK

Grb2adapter

p21 rasinactive

MAP kinases

jun

+ P

fos

+ P

jun fos

P P

myc Cyclin D

TK=Thyrosine kinase

3

p21 rasactive

AKT

Proliferationsignals

Glucosemetabolism

Energy

Protein synthesis

Anti-apoptosis

Enhanced angiogenesis

PTEN

-

MAP = Mitogen activated protein kinase

P

SH2

GEF

GEF = Guanine exchange factor

GDP GTP

GAP

GAP= GTPase activating protein

Apoptosis mechanismsApoptosis mechanisms

Mitochondria

BCL-2

Bax Bid

Cytochrome C AIF

Cytochrome C AIF

Caspases

Apoptosis

18

BadBik

P53

+

CathepsinD

TNF

FAS

Ceramide

Apoptosis

G1-checking point

p21

DeVita p.20056th Edition

Cyclin dependentKinase (cdk2)

Cyclin E}

RB E2F

RBP

E2F

Cell cycleactivation

Cycle arrest10

p16Cyclin dependentKinase (cdk4/6)

Cyclin D

}

Stop

Repair

Discard

G1-checking point

DNA break

MMR (Mismatch Repair Mechanisms)

ATM

P

BRCA2 RAD51

BRCA1 RAD52

Gene for repair ofdouble strand breaks

DeVita p.20056th Edition

p53

Apoptosis

Cyclin dependentKinase (cdk2)

Cyclin E

Cycle arrest

p21

hMutShMSH2hMSH6}

hMIH1hPMS2

hMutL

MLH1PMS1PMS2

Cyclin Dp16

cdk4

RbE2F

E2F

BRCA1 P

P

Growth stimulation

Repair

Stop

G1-checking point

DNA break

MMR (Mismatch Repair Mechanisms)

ATM

P

BRCA2 RAD51

BRCA1 RAD52

Gene for repair ofdouble strand breaks

DeVita p.20056th Edition

Cyclin dependentKinase (cdk2)

Cyclin E

Cycle arrest

p21

E2F

P

Growth stimulation

Repair

Stop

Apoptosis

hMutShMSH2hMSH6}

hMIH1hPMS2

hMutL

MLH1PMS1PMS2

BRCA1 P

p53

E2FRbCyclin D

p16cdk4

EndometriumOvaryBreastStomachSmall bowelPancreasHepato-biliaryRenal pelvisUreter

HNPCC

Turcot

LynchSyndr.

ColonEndometriumRenal pelvisUreterSmall bowelBreast

Li-FraumeniSyndr.

Breast CaSoft tissue Sa(Chilhood)OsteosarcomaBrain tumorsAdrenal CaAc. Leukemia

G1-checking point

DNA break

MMR (Mismatch Repair Mechanisms)

ATM

P

BRCA2 RAD51

BRCA1 RAD52

Gene for repair ofdouble strand breaks

DeVita p.20056th Edition

Cyclin dependentKinase (cdk2)

Cyclin E

Cycle arrest

p21

E2F

P

Growth stimulation

Repair

Stop

Apoptosis

hMutShMSH2hMSH6}

hMIH1hPMS2

hMutL

MLH1PMS1PMS2

BRCA1 P

p53

E2FRbCyclin D

p16cdk4

E6

E7

Papilloma virus

AgentsAgents

• Hepatitis B

• Hepatitis C

• HIV-1

• HTLV-1

• HPV

• Epstein-Barr

Site of CancerSite of Cancer

Liver

Liver

Kaposi’s sarcoma

Adult T-cell lymphoma

Uterine cervix

Burkitt’s lymphoma, nasopharynx,Hodgkin’s disease

Cole P, Rodu B. Cancer: Principles & Practice of Oncology. 6th ed. 2001;241-252.22

Virus-related cancers

Apoptosis mechanismsApoptosis mechanisms

Mitochondria

BCL-2

Bax Bid

Cytochrome C AIF

Cytochrome C AIF

Caspases

Apoptosis

23

BadBik

P53

+

CathepsinD

TNF

FAS

Ceramide