Post on 20-Jan-2015
description
11
Tumor Viruses and Cell Transformation-Tumor Viruses and Cell Transformation-Role in Cancer Initiation and PreventionRole in Cancer Initiation and Prevention
22
Tumor VirusesTumor VirusesTumor VirusesTumor Viruses
For most viruses:
Genome viral proteins
Replication Lysis Progeny virions
Lytic Life Cycle
33
Tumor VirusesTumor VirusesTumor VirusesTumor Viruses
Latent Life CycleVirus
Cell
Integration (usually)
Transformation
Virus-specific proteins expressed - No mature virus
Changes in the properties of host cell - TRANSFORMATION
4
Tumor VirusesTumor Viruses
Transformation:
Loss of growth control
Ability to form tumors - viral genes interfere with control of cell replication
5
TRANSFORMATIONBoth DNA and RNA tumor viruses can transform cells
Integration occurs (usually)
Similar mechanisms
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
These changes often result from the integration of the viral genome into the host cell DNA
6
TRANSFORMATION
Among the many altered properties of the TRANSFORMED CELL are:
• Loss of growth control (loss of contact inhibition in cultured cells)
• Tumor formation
• Mobility
• Reduced adhesion
• Transformed cells frequently exhibit chromosomal aberrations
77
Two Major Classes of Tumor Viruses
DNA Tumor Viruses
DNA viral genome
Host RNA polymerase
Viral mRNA
Viral protein
DNA-dependentDNA polymerase
(Host or viral)
88
RNA Tumor VirusesViral RNA genome
Reverse transcriptase (Virus-encoded)
Viral DNA genome (integrated)
DNA-dependent RNA polymerase (Host Host RNA pol II)
Viral genomic RNA
Splicing (Host splicing enzymes)
messenger RNA
viral protein
Virus
Important: Use HOSTRNA polymerase
to make its genome
An enzyme that normally
makes mRNA
IMPORTANT
9
DNA Tumor VirusesDNA Tumor Viruses
DNA genome
mRNA
protein
virus
Host RNA polymerase II
Host enzymes
OR TRANSFORMATIONIn transformation usually only EARLY functions are expressed
10
DNA Tumor Viruses In Human Cancer
Epidermodysplasia verruciformis
Papilloma virus
11
DNA Tumor Viruses In Human CancerDNA Tumor Viruses In Human Cancer
ONCOGENEA 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
12
DNA Tumor Viruses In Human CancerDNA Tumor Viruses In Human Cancer
Herpes Viruses
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Viral DNA found in small proportion of tumor cells: “hit and run” • Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis
• Transforms human B-lymphocytes in vitro
13
DNA Tumor Viruses In Human CancerDNA Tumor Viruses In Human Cancer
Hepatitis B Virus
DNA genome
RNA polymerase II
RNA Provirus
Reverse transcriptase
DNA genome
Host enzyme
Viral enzyme
14
DNA Tumor Viruses In Human CancerHepatitis 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
15
RNA Tumor VirusesRNA Tumor Viruses
RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus
REVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase
DNA genome
Integrase
Integrates
Host RNA polymerase II
RNA genome
virus
virus
host
16
RNA Tumor Viruses
RNA Tumor Viruses
17
RNA Tumor VirusesRNA Tumor Viruses
POL: Enzymes
Reverse transcriptase
Integrase
Protease
A normal retrovirus has:
3 genes
GAG : internal proteins
ENV: Envelope glycoproteins
18
RNA Tumor VirusesRNA Tumor VirusesRNA is:
• Diploid Capped and polyadenylated
• Positive sense (same as mRNA)
Viral RNA cannot be read as mRNA
New mRNA must be made
Virus must make negative sense DNA before proteins are made
Therefore virus must carry REVERSE TRANSCRIPTASE into the cell
19
RNA Tumor VirusesRNA Tumor Viruses
20
RNA Tumor VirusesRNA Tumor VirusesGroups of Retroviruses
• Oncovirinae
Tumor viruses and similar
• Lentiviruses
Long latent period
Progressive chronic disease
Visna HIV
• Spumavirinae
important
important
21
RNA Tumor VirusesRNA Tumor Viruses
• Human T cell lymphotropic virus -2 (HTLV-2)
Hairy cell leukemia
Retroviruses known to cause human cancer• Human T cell lymphotropic virus -1 (HTLV-1)
Adult T cell leukemia, Sezary T-cell leukemia
Africa, Caribbean, Some Japanese Islands
• HIV?
22
RNA Tumor VirusesRetrovirus Life Cycle
Endocytosis
Fusion of membranes
Release of nucleocapsid to cytoplasm
Nucleus
23
RNA Tumor VirusesRNA Tumor VirusesParental RNA
RNA/DNA Hybrid
Linear DNA/DNA duplex
Circular Duplex DNA
Integration Replication (DNA genome in cell)
Transcription Viral RNA genome mRNA protein
Reverse transcriptase
Reverse transcriptase
Integrase
Host RNA pol II
Host DNA polymerase
Host splicing enzymes
24
RNA Tumor VirusesDrawback to this lifestyle
Genomic RNA
DNA
Genomic RNA
Pol II is a host enzyme that, in the uninfected cell, makes mRNA
When making mRNA, pol II does not copy entire gene to RNA
Host RNA pol II
Reverse transcriptase
25
primer
Viral genomicRNA
Reverse transcriptase
dsDNA
promotor
RNA synthesis initiation site
RNA pol IIRNA synthesis termination
site
Result: New copy of viral RNA is shorter - lacks control sequences
Problem of using RNA pol II to copy a gene
RT
26
RNA Tumor VirusesRNA Tumor Viruses
Clue: Difference in the two forms
RNA
R U5 GAG POL ENV U3 R
LTR
Repeatregion
Repeatregion
DNA
U3 R U5 GAG POL ENV U3 R U5
27
Feline Sarcoma Virus (FSV)
R U5 dGAG FMS dENV U3 R
Avian Myelocytoma Virus (MC29)
R U5 dGAG MYC dENV U3 R
Avian Myeloblastosis Virus
R U5 GAG POL MYB U3 R
Some retroviruses have an oncogene instead of their regular genes
Some retroviruses have an oncogene instead of their regular genes
2828
RNA Tumor VirusesRNA Tumor VirusesRNA Tumor VirusesRNA Tumor Viruses
Viral Oncogene
V-onc
Cellular Proto-oncogene
C-onc
29
RNA Tumor VirusesRNA 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
30
RNA Tumor Viruses RNA Tumor Viruses
The discovery of the acutely transforming retroviruses that contain
v-oncs explains how cancers may arise as a result of infection
These viruses cause rapid cancer in animals in the laboratory
31
RNA Tumor VirusesRNA Tumor VirusesIn contrast:
Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
No oncogene! – How does it cause a tumor?
R U5 GAG POL ENV U3 R
Avian Leukosis Virus (causes lymphomas)
32
RNA Tumor VirusesRNA Tumor Viruses
Suggest tumor arose from one cell
• Something must be important about this site for transformation
• Crucial event must be rare
ALV can integrate into the host cell genome at MANY locations
but in tumor it is always at the SAME site (or restricted number of sites)
33
Cancers often result from gene translocationsCancers often result from gene translocations
Burkitt’s Lymphoma
8:14 translocation
Break in chromosome 14 at q32
Acute myelocytic leukemia
myc
34