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1 Tumor Viruses and Cell Tumor Viruses and Cell Transformation- Transformation- Role in Cancer Initiation and Role in Cancer Initiation and Prevention Prevention

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Tumor Viruses and Cell Transformation-Tumor Viruses and Cell Transformation-Role in Cancer Initiation and PreventionRole in Cancer Initiation and Prevention

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Tumor VirusesTumor VirusesTumor VirusesTumor Viruses

For most viruses:

Genome viral proteins

Replication Lysis Progeny virions

Lytic Life Cycle

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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

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Tumor VirusesTumor Viruses

Transformation:

Loss of growth control

Ability to form tumors - viral genes interfere with control of cell replication

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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

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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

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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)

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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

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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

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DNA Tumor Viruses In Human Cancer

Epidermodysplasia verruciformis

Papilloma virus

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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

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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

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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

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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

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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

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RNA Tumor Viruses

RNA Tumor Viruses

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RNA Tumor VirusesRNA Tumor Viruses

POL: Enzymes

Reverse transcriptase

Integrase

Protease

A normal retrovirus has:

3 genes

GAG : internal proteins

ENV: Envelope glycoproteins

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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

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RNA Tumor VirusesRNA Tumor Viruses

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RNA Tumor VirusesRNA Tumor VirusesGroups of Retroviruses

• Oncovirinae

Tumor viruses and similar

• Lentiviruses

Long latent period

Progressive chronic disease

Visna HIV

• Spumavirinae

important

important

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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?

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RNA Tumor VirusesRetrovirus Life Cycle

Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

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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

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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

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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

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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

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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

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RNA Tumor VirusesRNA Tumor VirusesRNA Tumor VirusesRNA Tumor Viruses

Viral Oncogene

V-onc

Cellular Proto-oncogene

C-onc

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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

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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

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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)

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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)

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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

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