Transcript Viruses and Cancer

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Viral Carcinogenesis
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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
Viruses and Cancer- History
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Oncogenes
Viral proteins at the checkpoints
Viruses and proliferation
Viruses and Immune suppression
Viral Carcinogenesis
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Provision of an oncogene
Insertional mutagenesis
Transcription Factor regulation
Immune suppression
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
RousSarcomaVirus and src oncogene
Viral Oncogenes
Location of functional effects
Secreted Growth Factors
• C sis analogous to PDGF
PDGF / c-sis signal transduction
PDGF/
c-sis
dimerize &
phosphorylate each
other
P
ras
MAPK
CELL
GROWTH
MAPK
P
phosphorlyates multiple
target proteins
Growth factor receptors
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erbB2 – EGFR /HER
Fms Colony stimulating factor r
Kit - stem cell growth factor receptor
All above are receptor tyrosine kinases
ErbB2
• Erb discovered in
avian erythroblastosis
• Homologous to EGF
receptors
• Truncated form
lacking part of
extracellular domain
• Permanent on-switch
Signalling through HER
• Depends on dimerisation
• Target for many drugs eg herceptin, iressa
• Effective anti-cancer therapies – watch space!
Signal transduction proteins
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Abl
Src
H-Ras
K-ras
Tyrosine Kinases as Cancer Drug
Targets
Src- linker protein
Ras family
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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
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
Transcription factors
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erbA
Fos
Jun
Rel
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Thyroid hormone r
AP-1 component
AP-1 component
NFkB homologue
How oncogenes go wrong
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Mutations
Amplifications
Translocation
Insertional mutagenesis
Activating Mutations in Ras Genes
Oncogene Translocation Events
Insertional Mutagenesis
LTR
LTR
MMTV
INT ( FGF)
mammalian
Gene Amplification
DNA virusses
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EBV
HBV
SV
Herpes Virusses
HPV
SV40 and p53
DNA-viral oncogenes
DNA Virus- derived oncogenes:
• Adenovirus:
E1A
pRB
E1B
p19
Apoptosis (anti)
p55
p53
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Polyoma virus (SV40):
T antigen
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pRB / p53
Papilloma virus:
E6
p53
E7
pRB (approx 75 HPVs)
DNA virus
• Repressor inactivation
• Promoter insertion c8/14 Burkitts myc /ig
lined up (EBV)
• Increased proliferation
• Effects on Transcriptional regulation
Papilloma virus and cancer
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Transcriptional Regulation by
Virusses
Hepatitis B virus and cancer
Multi-stage Carcinogenesis
But it’s not that simple!
Homer’s Lessons
• "You tried your best and failed miserably. The
lesson is 'never try'". H Simpson
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
HHV 8/ KSHV
• Bristling with subversive mechanisms
• Incorporates both growth factors and immune
regulatory molecules
• Emerges in the immune-suppressed host
HHV8 Immune subversion
HHV8 / KSHV and growth control
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Subverts cyclin
Retinoblastoma
P53
Angiogenic factors