Καρκινογένεση Εισαγωγή στις ογκογόνες οδούς σηματοδήτησης του κυττάρου Γιώργος Ρασιδάκης Επ. Καθηγητής Παθολογικής Ανατομικής, Ιατρική Σχολή ΕΚΠΑ Adj.

Παρουσίαση με θέμα: "Καρκινογένεση Εισαγωγή στις ογκογόνες οδούς σηματοδήτησης του κυττάρου Γιώργος Ρασιδάκης Επ. Καθηγητής Παθολογικής Ανατομικής, Ιατρική Σχολή ΕΚΠΑ Adj."— Μεταγράφημα παρουσίασης:

1 Καρκινογένεση Εισαγωγή στις ογκογόνες οδούς σηματοδήτησης του κυττάρου Γιώργος Ρασιδάκης Επ. Καθηγητής Παθολογικής Ανατομικής, Ιατρική Σχολή ΕΚΠΑ Adj. Assistant Professor, M.D. Anderson Cancer Center (USA)

2 Μεταλλάξεις γονιδίων –ογκογονίδια, ογκοκατασταλτικά γονίδια Δομικές βλάβες χρωμοσωμάτων –διαμεταθέσεις, απώλειες, προσθήκες Διαταραχές αριθμού χρωμοσωμάτων –ανευπλοειδία Καρκίνος  Γονιδιακή νόσος

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6 Table 4.6 The Biology of Cancer (© Garland Science 2007)

7 Figure 3.23b The Biology of Cancer (© Garland Science 2007)

8 Table 3.4 The Biology of Cancer (© Garland Science 2007)

9 Table 4.1 The Biology of Cancer (© Garland Science 2007)

10 Table 5.1 The Biology of Cancer (© Garland Science 2007)

11 Figure 5.11 The Biology of Cancer (© Garland Science 2007)

12 Figure 5.12a The Biology of Cancer (© Garland Science 2007)

13 Figure 5.12b The Biology of Cancer (© Garland Science 2007)

14 “ In the survival of favoured individuals and races, during the constantly-recurring struggle for existence, we see a powerful and ever-acting form of selection. ” Charles Darwin, 1859

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17 Interphase (12-24h, RNA and protein synthesis, cell growth) Gap 0 (G0) cell quit dividing temporarily or more permanently Gap 1 (G1) RNA and protein synthesis; G1 checkpoint S (synthesis) DNA replication Gap 2 (G2) protein synthesis and cell growth; G2 checkpoint Mitosis or M Phase (1-2h) division into two similar daughter cells; metaphase checkpoint Cell Cycle and Division

18 G1 G2 S Cell grows Cell division M DNA replication Cell prepares to divide C C C Metaphase checkpoint G1 checkpoint G2 checkpoint G0 Cells are responsive To mitogenic signals R

19 G2 S Cell grows Cell division M DNA replication Cell prepares to divide C C C Cyclin D1/2/3 Cdk4/6 RbE2F InactiveInactive P Rb P E2F Active S Phase Genes E2F DP Cyclin E Cdk2 Cyclin A Cdc2 Cyclin A Cdc2 Cyclin B INK4 p15,p16 p18,p19 INK4 p15,p16 p18,p19 CIP/KIP p21, p27 p57 CIP/KIP p21, p27 p57 G1

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22 Apoptosis Pathways Follicular Lymphoma t(14;18)

23 Σηματοδοτική οδός JAK / STAT

24 James E. Darnell, Jr., The Rockefeller University

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26 Jaks in hematopoiesis: phenotype of mouse knockouts Jak Type Relevant PhenotypesCytokines Affected Jak1 Impaired lymphoid developmentIL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL- 15, LIF, all interferons Defective responses to class 2 cytokines and those using c or gp130 receptor subunits Jak2 No definitive erythropoiesisEPO, TPO, IL-3, IL-5, GM-CSF, IFN- Jak3 Defective lymphoid developmentIL-4, IL-7, IL-9, IL-15 Dysregulated myelopoiesis EPO, erythropoietin; IFN, interferon; IL, interleukin; TPO, thrombopoietin

27 Stats in hematopoiesis: phenotypes of mouse knockouts Stat Type Relevant PhenotypesCytokines Affected Stat1 Interferon responses absent: innate immune responses absent highly sensitive to viral/microbial infection IFN- responsive genes not activated IFNs only Stat 2 Type 1 interferon responses impaired IFN- Stat 3 Embryonic lethal Stat 4 IL-12 responses absent production of high IFN-, low IFN- R Th1 cells priming for high level IFN- production lymphocyte proliferation enhancement of NK cell-mediated cytotoxicity Th2 cells IL-12 only Stat5ab Proliferation signaling affected: CFU-Mix, Eos, G, GM, Pre-B peripheral T cells Absence of NK cells IL-2, IL-3, IL-7, GM-CSF, G-CSF Stat6 IL-4 responses absent: -Absence of IL-4 producing Th2 cells -Block in B-cell IgE class switching lymphocyte proliferation (partial) expression of IL-4-induced cell surface markers IL-4 only CFU, colony-forming unit: G-CSF, granulocyte colony-stimulating factor; GM- CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; NK, natural killer.

28 Σηματοδοτική οδός PI3K / AKT / mTOR

29 Corradetti and Guan, Oncogene, 2006 Negative feedback loop mTOR-Rictor Activates AKT/PKB

30 Hay and Sonenberg, Genes Dev. 2004 mTOR Controls Translation Through Phosphorylation of p70S6K and 4E-BP1 mTOR

31 Hay and Sonenberg, Genes Dev. 2004 4E-BP1 Ribosome recruitment to mRNA (5’ end) eIF-4E binds the 5’ cap structure of mRNA 4E-BP1 PPPP

32 Σηματοδοτική οδός RAS / MEK / ERK

33 Figure 6.12a The Biology of Cancer (© Garland Science 2007)

34 Figure 6.14 The Biology of Cancer (© Garland Science 2007)

35 Figure 6.15 The Biology of Cancer (© Garland Science 2007)

36 AKT PI3K MEKMDM2 p53 RAS ERK mTOR PTEN survival GF- R RAF GF Proliferation BAD

37 AKT PI3K MEKMDM2 p53 RAS ERK mTOR PTEN Επιβίωση GF- R NF RAF GF Πολλαπλασιασμός Μεταλλάξεις RAS 20-50% Μεταλλάξεις PIK3CA 20% BAD Μεταλλάξεις BRAF Μεταλλάξεις p53 50%

38 PTEN TSC1/TSC2 Rheb AKT PI3K PDK1 PIP3 p70S6K4E-BP1 eIF4ErpS6 GβL mTOR RAPTOR GβL mTOR RICTOR Protein translation Flt3 GRB2 RAS ERK1/2 RAF1 MEK1/2 SHC SHIP SHP GAB2 GRB2 Cyclins (e.g. D1-3, A) CDK Inhibitors (e.g. p21, p27) JAK SHP1 SOCS SHP2 STAT3 Oncogenic kinases STAT3 Transcription

39 Σηματοδοτική οδός NFkB

40 Figure 6.29a The Biology of Cancer (© Garland Science 2007)

41 CD30 L CD30 TRADD TRAF IKK IKB  FADD FLICE Caspase 3 Anti-apoptosis Survival RIP DNA p52p65 NFkB c-FLIP Bcl-xL c-IAP TRAF1/2 XIAP p52p65 NFkB TNF-R DD apoptosis MAPK P P

42 Σηματοδοτική οδός Wnt / β-catenin

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47 Σηματοδοτική οδός Notch

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49 Ευχαριστώ