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Cell Cycle and CAncer

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

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Cell Cycle and CAncer

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011 ZoltanBalajthy MolecularTherapies-Lecture 12 CellCycle and CAncer

  3. TÁMOP-4.1.2-08/1/A-2009-0011 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 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 TÁMOP-4.1.2-08/1/A-2009-0011 12.1. The Functional Cell Cycle • 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)

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

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

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

  8. TÁMOP-4.1.2-08/1/A-2009-0011 Transcriptional Events in G1Phase of Cell-cycle CDK inhibitors Start of S phase DNS replication machinery pozitív erősítés Dihydrofolate reductase Thymidine kinase Thymidilate synthase DNA polymerase CDK inhibitors E2F: transcription factor E2F1 EGF: epidermal growth factor CDK: cyclin-dependent protein kinase Rb: retinoblastoma protein D1, A, E: Cyclin D1, A és E transzkripció leállítás DNS replication machinery CDK inhibitors

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

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

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

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

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

  15. P P P P TÁMOP-4.1.2-08/1/A-2009-0011 Ligand Binding Activates RTKs by Dimerization Ligand Receptor Homodimerization TGF-a EGF Ligand-binding Site Extracellular Domein Cytosolic Domein ATP EGFR-s (HER3,4) EGFR ADP Kinase Catalytic Site

  16. TÁMOP-4.1.2-08/1/A-2009-0011 Proto-oncogenesareNormal GenesThat Can Become Oncogenes

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

  18. TÁMOP-4.1.2-08/1/A-2009-0011 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 receptor Herceptin flags the cancer cells for destruction by theimmune system

  19. TKI TKI TÁMOP-4.1.2-08/1/A-2009-0011 12.6. Therapeutic Targets 1 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 2 3 4 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.

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

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