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Integration (often)
Transformation
VIRAL TRANSFORMATION
The changes in the biological functions of a cell that result from
REGULATION
of the cell’s metabolism by viral genes and that confer on the
infected cell certain properties characteristic of
NEOPLASIA
4
Tumor Viruses
• Both DNA and RNA tumor viruses can
transform cells
Viral protein
6
RNA Tumor Viruses
Viral RNA genome
Reverse transcriptase (Virus-encoded)
messenger RNA
Important: Use HOST
RNA polymerase
viral protein to make its genome
An enzyme that
normally
Virus
makes mRNA 7
DNA Tumor Viruses
DNA genome
Host RNA
polymerase II
mRNA
Host enzymes
protein
virus
OR TRANSFORMATION
In transformation usually only EARLY functions are expressed
8
DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
• cause natural cancers in animals
• cause benign warts
• ubiquitous
• epitheliotropic - most human tumors are malignancies of epithelial
cells
9
DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
• Epidermodysplasia verruciformis
wart malignant
skin squamous cell carcinoma
10
DNA Tumor Viruses In
Human Cancer
Epidermodysplasia
verruciformis
Papilloma virus
© 2008
Dermatology
Online Journal
11
DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
urogenital cancer
wart malignant squamous cell carcinoma
Effective Vaccine
(quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in
yeast - Gardasil) 13
Papilloma Viruses
• The important transforming genes in
papilloma viruses are: E6 and E7
• Early genes - Not encoding structural
proteins
• Oncogenes
14
DNA Tumor Viruses In
Human Cancer
Polyoma Viruses
• Simian virus 40 - juvenile hamster sarcomas, transformation
• Polyoma - mouse leukemia, in vitro transformation
• Human polyomas (JC and BK) - monkey sarcoma, transformation
Possible association of BK with human prostate cancer
15
JC: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
DNA Tumor Viruses In
Human Cancer
Adenoviruses
Highly oncogenic in animals
Only part of virus integrated
• Papilloma: E6 and E7
• Polyoma: Large T and small T antigen
• Adenovirus: E1A and E1B
17
DNA Tumor Viruses In
Human Cancer
ONCOGENE
A gene that codes for a protein that potentially can transform
a normal cell into a malignant cell
An oncogene may be transmitted by a virus in which case it is
known as a VIRAL ONCOGENE
v-onc
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DNA Tumor Viruses In
Human Cancer
Herpes Viruses
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Integrated viral DNA found in small proportion of tumor cells:
“hit and run”
19
DNA Tumor Viruses In
Human Cancer
Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis (glandular fever)
• Transforms human B-lymphocytes in vitro
Hematologic malignancies
RNA Provirus
Reverse transcriptase
Viral enzyme
DNA genome
22
DNA Tumor Viruses In
Human Cancer
Hepatitis B continued
•Long latency
23
DNA Tumor Viruses In
Human Cancer
Hepatitis B continued
Epidemiology:
• Strong correlation between
HBV and hepatocellular
carcinoma
• China: 500,000 - 1 million new
cases of hepatocellular carcinoma
per year
• Taiwan: Relative risk of getting
HCC is 217 x risk of non-carriers
24
DNA Tumor Viruses In
Human Cancer
Summary
DNA genome
Integrase virus
Integrates
Host RNA polymerase II host
RNA genome 26
RNA Tumor
Viruses
27
RNA Tumor Viruses
A normal retrovirus has:
3 genes
GAG : internal proteins
ENV: Envelope glycoproteins
POL: Enzymes
Reverse transcriptase – RNase H
Integrase
28
Protease
RNA Tumor Viruses
RNA is:
• Diploid Capped and polyadenylated
• Positive sense (same as mRNA)
Viral RNA cannot be read as mRNA
(even though same sense)
New mRNA must be made
Virus must make negative sense DNA before proteins are
made
Therefore virus must carry REVERSE TRANSCRIPTASE
29
into the cell
RNA Tumor Viruses
30
RNA Tumor Viruses
Groups of Retroviruses
• Oncovirinae important
32
RNA Tumor Viruses
Human T cell lymphotropic virus -1 (HTLV-1)
UNITED STATES AND OTHER WESTERN COUNTRIES
IV DRUG USERS
US rate of infection about one tenth of that of HIV
BUT half as prevalent as HIV in IV drug users
• HIV ? 34
RNA Tumor Viruses
Retrovirus Life Cycle
Bind to Endocytosis
surface receptor
Fusion of membranes
Nucleus
35
RNA Tumor Viruses
Parental RNA
Reverse transcriptase
RNA/DNA Hybrid
Reverse
transcriptase
Linear DNA/DNA duplex
Genomic RNA
Reverse transcriptase
DNA
Host RNA pol II
Genomic RNA
When making mRNA, pol II does not copy entire gene to RNA
37
Problem of using RNA pol II to copy a gene
RT Viral
primer genomicRNA
Reverse
transcriptase
dsDNA
RNA synthesis
initiation site
promotor
RNA pol II
RNA synthesis termination
site
38
Result: New copy of viral RNA is shorter - lacks control sequences
RNA Tumor Viruses
RNA polymerase II will not copy
Upstream sequences from transcription initiation site
• Promotors / Enhancers
Down stream sequences from transcription termination site
• Enhancers / Poly A site / termination site
?
Perhaps virus could integrate downstream of a promotor etc so
that the cell provides sequences
OR
Virus provides its own promotors etc
39
BUT not copied!
RNA Tumor Viruses
Repeat Repeat
region region
Clue: Difference in the two forms
RNA
DNA
LTR LTR 40
R U5 Viral RNA U3 R
Reverse
transcriptase
U3 R U5 U3 R U5
Long terminal repeats are formed
promotor
POLII POLII
LTR LTR
POLII POLII
“typical retrovirus”
44
R U5 dGAG MYC dENV U3 R
RNA Tumor Viruses
Viral Oncogene
V-onc
Cellular Proto-oncogene
C-onc
45
RNA Tumor Viruses
Proto-oncogene
A cellular (host) gene that is homologous with a
similar gene that is found in a transforming virus
A cellular oncogene can only induce
transformation after
• mutation
• some other change in the cell’s genome 46
RNA Tumor Viruses
The discovery of the acutely transforming
retroviruses that contain
v-oncs explains how cancers may arise as a result
of infection
47
RNA Tumor Viruses
In contrast:
Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
Avian Leukosis Virus (causes lymphomas)
It is close to
C-myc!
Oncogenesis by promotor insertion
50
RNA Tumor Viruses
51
RNA Tumor Viruses
What do oncogenes encode?
Proteins that are involved in growth control and
differentiation
Growth factors
Growth factor receptors
Signal transduction proteins
Transcription factors
52
DNA Tumor Viruses
How they tumors depended on
our knowledge of RNA tumor
viruses
53
DNA Tumor Viruses
Herpes
Genes can be
assigned to
sites on
specific
myb mos
chromosomes
myc
myc
58
Function gained Function gained
Anti-Oncogenes
Recessive mutations
Mutation growth
Rb
Rb protein
Heterozygote Homozygote
Rb Function lost
Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomas 60
Anti-Oncogenes
P53
Inactivated by
• deletion
• point mutation
61
DNA Tumor Viruses
Oncogenes
• Adenovirus E1A region 2
• SV 40 Large T
• Polyoma Large T
• BK virus Large T
• Lymphotropic virus Large T
• Human papilloma Virus-16 E6, E7
Rb Rb
protein 105kD
Rb
Rb
63
Stops replication Cell cycle continues
Anti-Oncogenes
p53
P53 gene P53 gene P53 gene
Hepatitis C Papilloma
Papilloma
proteolysis
P53 DNA
64
Stops replication replication replication