Viral Carcinogenesis

2. 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

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

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

5. 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

6. RousSarcomaVirus and src oncogene

8. Viral Oncogenes

9. Location of functional effects

10. Secreted Growth Factors • C sis analogous to PDGF

11. 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

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

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

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

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

16. Tyrosine Kinases as Cancer Drug Targets

17. Src- linker protein

19. 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

20. 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

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

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

23. Activating Mutations in Ras Genes

24. Oncogene Translocation Events

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

27. Gene Amplification

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

29. SV40 and p53

30. DNA-viral oncogenes

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

32. Papilloma virus and cancer

34. Transcriptional Regulation by Virusses

35. Hepatitis B virus and cancer

37. Multi-stage Carcinogenesis

38. But it’s not that simple!

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

41. 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

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

43. HHV8 Immune subversion

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