Transcript E2F
@derka 1 An explanation should be as simple as possible but not a bit simpler… Albert Einstein 2 Erythropoietin EGF HGF IGF NGF Estrogen Testosterone VEGF To be or not to be…an intracellular drama A computo-novella Growth factors G0 TK=Thyrosine kinase Enhanced angiogenesis EGF EGF receptor TK SH2 - G1 checking point Protein synthesis PTEN Grb2 adapter GEF GDP Anti-apoptosis AKT TK P GEF = Guanineexchange factor Proliferation signals Glucose metabolism Energy GTP p21 ras inactive p21 ras active +P jun GAP MAP kinases P P jun fos myc Cyclin D fos +P Functiona l signifi ca nce of genes i n mel a noma DeVita p.2005 6th Editio n GAP= GTPase activating protein MAP = Mitogen activated protei n kinase 3 + p53 BRCA2 p27 p18 2 p19 RAD52 p16 } hMutS Apoptosis Apoptosis mechanisms mechanisms Apoptosis DNA break ir Repa RAD51 } TNF RB E2F INK4 family p15 hMSH2 hMSH6 Gene for repair of double st rand breaks cip/kip family Cyclin E hMutL MLH1 PMS1 PMS2 BRCA1 P Cyclin dependent Kinase (cdk2) } P BRCA1 p21 hMIH1 hPMS2 ATM + p57 Growth receptors media ted growth sti mula tion MMR (Mismatch Repair Mechanisms) Apoptosis Cyclin dependent Kinase (cdk4/6) E2F } Cyclin D Cycle arrest P RB Mitochondria BCL-2 FAS Cell cycle activation TGF- NEJM 342:1350,2000 Bax + Caspases Bid Bad Bik Ceramide Cytochrome CC Cytochrome AIF AIF Apoptosis P53 Mitosis CathepsinD 18 G2-checking point S phase 5 TK=Thyrosine kinase Antiangiogenic factors Enhanced angiogenesis GEF = Guanine exchange factor EGF Herceptin Iressa Akt/PKB=Protein kinase B Erbitux TK EGF receptor P Grb2 adapter GEF GDP Anti-apoptosis Akt/PKB Ribosome biosynthesis Proliferation signals Glucose metabolism Protein synthesis Energy GTP p21 ras inactive p21 ras active +P jun GAP MAP kinases P P jun fos myc Cyclin D fos +P GAP= GTPase activating protein MAP = Mitogen activated protein kinase 6 Cell proliferation EGF 50 000 Normal cell 1:20 Her2 EGF-R 2 ras MAPK Akt 1 000 000 To be or not to be…an intracellular drama A computo-novella Growth factors G0 TK=Thyrosine kinase Enhanced angiogenesis EGF EGF receptor TK SH2 - G1 checking point Protein synthesis PTEN Grb2 adapter GEF GDP Anti-apoptosis AKT TK P GEF = Guanineexchange factor Proliferation signals Glucose metabolism Energy GTP p21 ras inactive p21 ras active +P jun GAP MAP kinases P P jun fos myc Cyclin D fos +P Functiona l signifi ca nce of genes i n mel a noma DeVita p.2005 6th Editio n GAP= GTPase activating protein MAP = Mitogen activated protei n kinase 3 + p53 BRCA2 p27 p18 2 p19 RAD52 p16 } hMutS Apoptosis Apoptosis mechanisms mechanisms Apoptosis DNA break ir Repa RAD51 } TNF RB E2F INK4 family p15 hMSH2 hMSH6 Gene for repair of double st rand breaks cip/kip family Cyclin E hMutL MLH1 PMS1 PMS2 BRCA1 P Cyclin dependent Kinase (cdk2) } P BRCA1 p21 hMIH1 hPMS2 ATM + p57 Growth receptors media ted growth sti mula tion MMR (Mismatch Repair Mechanisms) Apoptosis Cyclin dependent Kinase (cdk4/6) E2F } Cyclin D Cycle arrest P RB Mitochondria BCL-2 FAS Cell cycle activation TGF- NEJM 342:1350,2000 Bax + Caspases Bid Bad Bik Ceramide Cytochrome CC Cytochrome AIF AIF Apoptosis P53 Mitosis CathepsinD 18 G2-checking point S phase 9 DeVita p.2005 6th Edition G1-checking point p21 Cyclin dependent Kinase (cdk2) Cyclin E } RB E2F p16 Cyclin dependent Kinase (cdk4/6) E2F } Cyclin D 10 Cycle arrest P RB Cell cycle activation Discard Stop Repair DeVita p.2005 6th Edition MMR (Mismatch Repair Mechanisms) G1-checking point Apoptosis ATM hMIH1 hPMS2 P BRCA1 P Gene for repair of double strand breaks p53 BRCA1 hMSH2 hMSH6 hMutL MLH1 PMS1 PMS2 } hMutS RAD52 DNA break RAD51 p21 Cyclin dependent Kinase (cdk2) Cyclin E p16 Stop cdk4 E2F Cyclin D Rb P E2F Cycle arrest Growth stimulation DeVita p.2005 6th Edition MMR (Mismatch Repair Mechanisms) G1-checking point Apoptosis ATM hMIH1 hPMS2 P BRCA1 P Gene for repair of double strand breaks p53 BRCA1 hMSH2 hMSH6 hMutL MLH1 PMS1 PMS2 } hMutS RAD52 DNA break RAD51 p21 Cyclin dependent Kinase (cdk2) Cyclin E p16 Stop cdk4 E2F Cyclin D Rb P E2F Cycle arrest Growth stimulation Endometrium Ovary Breast Stomach Lynch Small bowel Syndr. Pancreas Hepato-biliary Renal pelvis Ureter Turcot HNPCC Colon Endometrium Renal pelvis Ureter Small bowel Breast Li-Fraumeni Syndr. Breast Ca Soft tissue Sa (Chilhood) Osteosarcoma Brain tumors Adrenal Ca Ac. Leukemia DeVita p.2005 6th Edition MMR (Mismatch Repair Mechanisms) G1-checking point Apoptosis ATM hMIH1 hPMS2 P BRCA1 p53 P Gene for repair of double strand breaks E6 BRCA1 hMSH2 hMSH6 hMutL MLH1 PMS1 PMS2 } hMutS RAD52 DNA break RAD51 p21 Cyclin dependent Kinase (cdk2) Cyclin E p16 cdk4 E2F Cyclin D Rb P E7 Stop Papilloma virus E2F Cycle arrest Growth stimulation Virus-related cancers 22 Agents Site of Cancer • Hepatitis B Liver • Hepatitis C Liver • HIV-1 Kaposi’s sarcoma • HTLV-1 Adult T-cell lymphoma • HPV Uterine cervix • Epstein-Barr Burkitt’s lymphoma, nasopharynx, Hodgkin’s disease Cole P, Rodu B. Cancer: Principles & Practice of Oncology. 6th ed. 2001;241-252. Apoptosis mechanisms TNF FAS Mitochondria BCL-2 Bax Bid Caspases Bad Bik Ceramide + P53 Cytochrome C AIF CathepsinD 23 Apoptosis