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Viral Carcinogenesis

RNA Rous Sarcoma src Rat Sarcoma ras Erythroblastosis erb Feline osteosarcoma fos Simian sarcoma MMTV. DNA Human Papilloma E6/7 p53 RB Adenovirus E1A / EiB SV40 T Rb p53 EBV p53 myc HBV X – p53. Viral Carcinogenesis. Viruses and Cancer- History. Oncogenes

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Viral Carcinogenesis

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  1. RNA Rous Sarcoma src Rat Sarcoma ras Erythroblastosis erb Feline osteosarcoma fos Simian sarcoma MMTV DNA Human Papilloma E6/7 p53 RB Adenovirus E1A / EiB SV40 T Rb p53 EBV p53 myc HBV X – p53 Viral Carcinogenesis

  2. Viruses and Cancer- History • Oncogenes • Viral proteins at the checkpoints • Viruses and proliferation • Viruses and Immune suppression

  3. Viral Carcinogenesis • Provision of an oncogene • Insertional mutagenesis • Transcription Factor regulation • Immune suppression

  4. Viral Oncogenes and Cancer • Cellular origin of viral oncogenes—oncogenes carried by transforming retroviruses are derived from cellular genes • oncogenes involved in cancer development are aberrant versions of normal cell genes that function in growth control

  5. RousSarcomaVirus and src oncogene

  6. Viral Oncogenes

  7. Location of functional effects

  8. Secreted Growth Factors • C sis analogous to PDGF

  9. PDGF / c-sis signal transduction PDGF/c-sis d i m e r i z e & P p h o s p h o r y l a t e e a c h r a s o t h e r M A P K M A P K P C E L L p h o s p h o r l y a t e s m u l t i p l e t a r g e t p r o t e i n s G R O W T H

  10. Growth factor receptors • erbB2 – EGFR /HER • Fms Colony stimulating factor r • Kit - stem cell growth factor receptor • All above are receptor tyrosine kinases

  11. ErbB2 • Erb discovered in avian erythroblastosis • Homologous to EGF receptors • Truncated form lacking part of extracellular domain • Permanent on-switch

  12. Signalling through HER • Depends on dimerisation • Target for many drugs eg herceptin, iressa • Effective anti-cancer therapies – watch space!

  13. Signal transduction proteins • Abl • Src • H-Ras • K-ras

  14. Tyrosine Kinases as Cancer Drug Targets

  15. Src- linker protein

  16. Ras family • H-ras, K-ras, N-ras • Encodes three small G-proteins • Activated by binding GTP • Inactivated by GTP hydrolysis • Mutant forms constitutively active • Active forms lead to cell growth

  17. Growth factor sis Simian sarcoma virus SSV Monkey Platelet-derived growth factor G protein H-ras Harvey murine sarcoma virus Ha-MSV Rat GDP/GTP binding K-ras Kirsten murine sarcoma virus Ki-MSV Rat GDP/GTP binding

  18. erbA Fos Jun Rel Thyroid hormone r AP-1 component AP-1 component NFkB homologue Transcription factors

  19. How oncogenes go wrong • Mutations • Amplifications • Translocation • Insertional mutagenesis

  20. Activating Mutations in Ras Genes

  21. Oncogene Translocation Events

  22. Insertional Mutagenesis INT ( FGF) LTR LTR mammalian MMTV

  23. Gene Amplification

  24. DNA virusses • EBV • HBV • SV • Herpes Virusses • HPV

  25. SV40 and p53

  26. DNA-viral oncogenes

  27. DNA virus • Repressor inactivation • Promoter insertion c8/14 Burkitts myc /ig lined up (EBV) • Increased proliferation • Effects on Transcriptional regulation

  28. Papilloma virus and cancer

  29. Transcriptional Regulation by Virusses

  30. Hepatitis B virus and cancer

  31. Multi-stage Carcinogenesis

  32. But it’s not that simple!

  33. Homer’s Lessons • "You tried your best and failed miserably. The lesson is 'never try'". H Simpson

  34. HIV and Kaposi Sarcoma • Vascular tumour of spindle cells • Associated with HIV infection and TH activation • Mediated through HHV8 • HHV8 results in increased cytokine production and growth • Angiogenic factors induced

  35. HHV 8/ KSHV • Bristling with subversive mechanisms • Incorporates both growth factors and immune regulatory molecules • Emerges in the immune-suppressed host

  36. HHV8 Immune subversion

  37. HHV8 / KSHV and growth control • Subverts cyclin • Retinoblastoma • P53 • Angiogenic factors

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