1. Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. CELL CYCLE AND CANCER Zoltan Balajthy Molecular Therapies- Lecture 12 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

3. Learning objectives of chapter 12 and 13. The purpose of this chapter is to describe the processes and regulations of both cell cycle and cell death, explain the unregulated cell division, and to point out the therapeutic intervention in cancer at molecular levels. Topics in chapter 12. 12.1. Interpretation of cell cycle Constitutive and Inducible Cell Cycle Kinase Inhibitors 12.2. Mitogen-activated Protein (MAP) Kinase Cascade Transcriptional Events in G1 Phase of Cell-cycle Mechanisms of Gene-suppression by the Retinoblastoma Protein 12.3. Biochemical Events of Cell-cycle – in M Phase 12.4. Cancer Causing Genes in Mitotic Signal Pathway Proto-oncogenes and Oncogenes TÁMOP-4.1.2-08/1/A-2009-0011 12.5. Different Families of Receptor Tyrosine Kinases (RTK) Proto-oncogenes are normal genes that can become oncogenes 12.6. Therapeutic Targets Monoclonal antibodies and specific inhibitors

4. Checkpoints controll The conventional cell cycle is modified to indicate : - G1 activities, those preparatory for S phase, may begin during the previous cycle, concurrently with G2 and mitotic events. - early preparation for mitosis (G2) may overlap with S - exit from G1 into the G0 quiescent state and reentry into the cycle The critical points: C (indicating competence), V (end of entry) R (restriction point, end of progression) 12.1. The Functional Cell Cycle TÁMOP-4.1.2-08/1/A-2009-0011

5. Cyclin-CDK Regulators of Cell-Cycle TÁMOP-4.1.2-08/1/A-2009-0011

6. cell divison cycle: CDC, cyclin-dependent protein kinases: CDK cyclin-dependent protein kinases inhibitor: CDI, CDK1 CKIs DNA damade, starvation or factor inducible DNA-damage inducible Constitutive CKI Constitutive CKI APC Constitutive and Inducible Cell Cycle Kinase Inhibitors, and are check points at the „s”, „gm”, and „m” stable states TÁMOP-4.1.2-08/1/A-2009-0011

7. 12.1. Mitogen-activated Protein (MAP) Kinase Cascade TÁMOP-4.1.2-08/1/A-2009-0011

8. CDK inhibitors Dihydrofolate reductase Thymidine kinase Thymidilate synthase DNA polymerase E2F: transcription factor E2F1 EGF: epidermal growth factor CDK: cyclin-dependent protein kinase Rb: retinoblastoma protein D1, A, E: Cyclin D1, A és E DNS replication machinery Start of S phase pozitív erősítés transzkripció leállítás Transcriptional Events in G1 Phase of Cell-cycle DNS replication machinery TÁMOP-4.1.2-08/1/A-2009-0011

9. Mechanisms of Gene-suppression by the Retinoblastoma Protein TÁMOP-4.1.2-08/1/A-2009-0011

10. 11.3. Biochemical Events of Cell-cycle – in M Phase TÁMOP-4.1.2-08/1/A-2009-0011

11. 12.4. Cancer Causing Genes in Mitotic Signal Pathway TÁMOP-4.1.2-08/1/A-2009-0011

12. Proto-oncogenes and Oncogenes TÁMOP-4.1.2-08/1/A-2009-0011

13. Possible Biochemical Mechanisms of Protooncogene - oncogene Conversion - promoter insertion - enhancer insertion - chromosomal translocation - gene amplification - single point mutation or deletion Out the 5 mechanisms described above, the first 4 involve an increase in amount of the product of an oncogene due to increased transcription but no alteration of the structure of the product of the oncogene. Thus it appears that increased amounts of the product of an oncogene may be sufficient to push a cell becoming malignant. The fifth mechanism, single point mutation, involves a change in the structure of the product of the oncogene but not necessarily any change in its amount. This implies that the presence of a structurally abnormal key regulatory protein in a cell may be sufficient to tip the scale toward malignancy. TÁMOP-4.1.2-08/1/A-2009-0011

14. EGFR (HER 2,3,4 TGF-  EGF IGF-1R P P P P IGF-1 IGF-2 PDGFR PDGF VEGF-A VEGF-B VEGFR HER2 None EGFR/HER2 P P P P Receptor Heterodimerization and Activation 12.5. Different Families of Receptor Tyrosine Kinases (RTK) Recognize a Diverse Set of Different Ligands Transmembrane Lipophilic Segment Intracellular Protein Tyrosine Kinase Domain Extracellular Binding Domain TÁMOP-4.1.2-08/1/A-2009-0011

16. Proto-oncogenes are Normal Genes That Can Become Oncogenes TÁMOP-4.1.2-08/1/A-2009-0011

17. mAbs L XX Signal transductiom X L XX Signal transductiom X L Tyrosine kinase inhibitors (TKI) TKI L L ✝ ✝ Cell death Toxin-induced cell death L L RNA interference Protein synthesis X Neu, EGFR-targeting Methods TÁMOP-4.1.2-08/1/A-2009-0011

18. Expression of HER2 Receptor on the Surface of Normal and Tumor Cells Herceptin Binds to the HER2 Receptor on the Surface of Tumor Cells Normal expression of HER2 receptor Increased expression of HER2 receptor Herceptin attaches itself to HER2 receptorHerceptin flags the cancer cells for destruction by the immune system TÁMOP-4.1.2-08/1/A-2009-0011

19. 1, blocking signalization on cell surface receptor 2, inhibition of TK activity of TKR 3, inhibition of protein kinases phosphorilation cascade 4, activation of growths-inhibiting pathway (Rb) or restoration of p53 function 5, inhibition of angiogenesis 6, inhibition of methastasis In addition to the classical form of cancer treatment: like surgery, chemotherapy and radiotherapy, there are new therapeutic targets at molecular level against cancer cells. 1 TKI 2 3 4 12.6. Therapeutic Targets TÁMOP-4.1.2-08/1/A-2009-0011

20. Blocking of Oncoproteins of EGFR and Mitogen-activated Protein Kinase Signalization via Monoclonal abs. and Specific Inhibitors TÁMOP-4.1.2-08/1/A-2009-0011