@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 dramaA computo-novella Mitosis Growth factors Apoptosis

EGF receptor EGF TK TK=Thyrosine kinase 6 Enhanced angiogenesis Proliferation signals MAP kinases MAP = Mitogen activated protein kinase Grb2 adapter P GEF GEF = Guanine exchange factor p21 ras inactive GDP p21 ras active GTP GAP GAP= GTPase activating protein Anti-apoptosis Glucose metabolism Energy Protein synthesis Ribosome biosynthesis jun + P fos + P junfos PP myc Erbitux Iressa Herceptin Antiangiogenic factors Cyclin D Cell proliferation Akt/PKB Akt/PKB=Protein kinase B

EGF-R 2 Akt ras MAPKHer2 Normal cell EGF :20

9 G0 G1 checking point S phase G2-checking point To be or not to be…an intracellular drama Growth factors A computo-novella Mitosis Apoptosis

G1-checking point p21 DeVita p th Edition Cyclin dependent Kinase (cdk2) Cyclin E } RB E2F RB P E2F Cell cycle activation Cycle arrest 10 p16 Cyclin dependent Kinase (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 of double strand breaks DeVita p th Edition p53 Apoptosis Cyclin dependent Kinase (cdk2) Cyclin E Cycle arrest p21 hMutS  hMSH2 hMSH6 } hMIH1 hPMS2 hMutL  MLH1 PMS1 PMS2 Cyclin D p16 cdk4 Rb 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 of double strand breaks DeVita p th Edition Cyclin dependent Kinase (cdk2) Cyclin E Cycle arrest p21 E2F P Growth stimulation Repair Stop Apoptosis hMutS  hMSH2 hMSH6 } hMIH1 hPMS2 hMutL  MLH1 PMS1 PMS2 BRCA1 P p53 E2F Rb Cyclin D p16 cdk4

Endometrium Ovary Breast Stomach Small bowel Pancreas Hepato-biliary Renal pelvis Ureter HNPCC Turcot Lynch Syndr. Colon Endometrium Renal pelvis Ureter Small bowel Breast

Li-Fraumeni Syndr. Breast Ca Soft tissue Sa (Chilhood) Osteosarcoma Brain tumors Adrenal Ca Ac. Leukemia

G1-checking point DNA break MMR (Mismatch Repair Mechanisms) ATM P BRCA2 RAD51 BRCA1 RAD52 Gene for repair of double strand breaks DeVita p th Edition Cyclin dependent Kinase (cdk2) Cyclin E Cycle arrest p21 E2F P Growth stimulation Repair Stop Apoptosis hMutS  hMSH2 hMSH6 } hMIH1 hPMS2 hMutL  MLH1 PMS1 PMS2 BRCA1 P p53 E2F Rb Cyclin D p16 cdk4 E6 E7 Papilloma virus

Agents Hepatitis B Hepatitis C HIV-1 HTLV-1 HPV Epstein-Barr Site of Cancer 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; Virus-related cancers

Apoptosis mechanisms Mitochondria BCL-2 Bax Bid Cytochrome C AIF Cytochrome C AIF Caspases Apoptosis 23 Bad Bik P53 + CathepsinD TNF FAS Ceramide