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G2 / M phase transition is performed by a protein kinase conserved throughout eukaryotes

Cell Cycle = round of chromosomal replication in S phase followed by segregation of the replicated chromosomes into two daughter nuclei during M phase. G2 / M phase transition is performed by a protein kinase conserved throughout eukaryotes MPF - protein kinase catalytic subunit p34 cdc2

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G2 / M phase transition is performed by a protein kinase conserved throughout eukaryotes

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  1. Cell Cycle = round of chromosomal replication in S phase followed by segregation of the replicated chromosomes into two daughter nuclei during M phase

  2. G2 / M phase transition is performed by a protein kinase conserved throughout eukaryotes MPF - protein kinase catalytic subunit p34 cdc2 - B-type cyclin

  3. RESTRICTION POINT Cells no longer require presence of serum to commit themselves to initiating DNA replication

  4. CELL CYCLE

  5. Uncontrolled cell proliferation requires multi-step gene damage eg gain of function of oncogenes (accelerator) and loss of function of tumour suppressors (brakes) Oncogene Tumour suppressor CYCLINS CDKI

  6. P E2F pRB pRB E2F NORMAL CELL CYCLE TS

  7. Viral Targeting of pRb T Ag HPVE7pRB E1A

  8. INACTIVATION OF pRB in TUMORS • retinoblastoma • small-cell lung cancer • soft tissue sarcoma • glioblastoma • breast cancer • bladder carcinoma

  9. Proliferation E2FApoptosis

  10. POSITIVE REGULATORS OF G1 PHASE PROGRESSION

  11. CDK-CYCLIN COMPLEXES • Intrinsically inactive catalytic subunit (CDK) • Positive regulatory subunit (cyclin) • Phosphorylation of conserved threonine residue

  12. CDK-ACTIVATING KINASE • phosphorylates cyclin-bound CDK on threonine • multisubunit enzyme with catalytic subunit (CDK7) and regulatory subunit (cyclin H) • invariant throughout cell cycle

  13. CYCLIN D • 3 Cyclin D genes • synthesised by mid-G1 phase and maximum at G1/S boundary • stimulated by growth factors • promote catalytic activity of CDK4 and CDK6

  14. CYCLIN E • synthesis at late G1 phase • complexes with CDK2 • ectopic overproduction contracts G1, reduces cell size and decreases cellular dependency on mitogenic growth factors

  15. NEGATIVE REGULATORS OF G1 PHASE PROGRESSION

  16. CYCLIN-DEPENDENT KINASE INHIBITORS p21cip1 CIP/KIP p27kip1 p57kip2 p16INK4a p15INK4b INK4 p18INK4c p19INK4d

  17. INK4 CDKI • specifically target CDK’s • INK4 proteins sequester cdk4/6 into complexes liberating cip/kip proteins • ability to arrest in G1 dependent on intact pRb

  18. Cip/Kip CDKI • p21= waf1=Sdi1 inhibits cyclin/CDK function through cell cycle • p27kip1 bound to cyclin/CDK4;

  19. CELL CYCLE GENE ALTERATIONS IN CANCER • pRb deletion / mutation • p16 deletion / mutation • p27 inactivation (methylation) • cyclin D1 overexpression • cyclin E overexpression • CDK4 overexpression

  20. Keyomarsi et al N Engl J Med. 2002

  21. p53 MDM2 CELL CYCLE PROGRESSION

  22. SERINE-15 P ATM p53 MDM2 CELL CYCLE ARREST

  23. Increasing endogenous CDK inhibition Proteasome inhibitor PS-341 20S proteasome Histone deacetylase inhibitors Altering cyclin levels Flavopiridol Cyclin D Rapamycin (CCI-779) Cyclins D and A

  24. Direct inhibitors of cyclin-dependent kinases Flavopiridol CDK1, 2, 4 UCN-01/staurosporine CDK1, 2, 4, PKC, chk1

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