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For most viruses: Genome viral proteins. Replication Lysis Progeny virions . Tumor Viruses. Lytic Life Cycle. Tumor Viruses. Latent Life Cycle Virus Cell Integration (usually) Transformation

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tumor viruses

For most viruses:

Genome viral proteins

Replication Lysis Progeny virions

Tumor Viruses

Lytic Life Cycle

tumor viruses2
Tumor Viruses

Latent Life Cycle

Virus

Cell

Integration (usually)

Transformation

Virus-specific proteins expressed - No mature virus

Changes in the properties of host cell - TRANSFORMATION

tumor viruses3
Tumor Viruses

Transformation:

Loss of growth control

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

slide4

TRANSFORMATION

Both 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

slide5

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
slide6

Two Major Classes of Tumor Viruses

DNA Tumor Viruses

DNA viral genome

DNA-dependentDNA polymerase(Host or viral)

Host RNA polymerase

Viral mRNA

Viral protein

slide7

RNA Tumor Viruses

Viral RNA genome

Reverse transcriptase (Virus-encoded)

Viral DNA genome (integrated)

DNA-dependent RNA polymerase (Host RNA pol II)

Viral genomic RNA

Splicing (Host splicing enzymes)

messenger RNA

viral protein

Virus

IMPORTANT

Important: Use HOSTRNA polymerase to make its genome

An enzyme that normallymakes mRNA

dna tumor viruses
DNA Tumor Viruses

DNA genome

mRNA

protein

virus

Host RNA polymerase II

Host enzymes

OR TRANSFORMATIONIn transformation usually only EARLY functions are expressed

dna tumor viruses in human cancer
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
dna tumor viruses in human cancer10

Papilloma Viruses

  • epidermodysplasia verruciformis
  • wart malignant squamous cell carcinoma
DNA Tumor Viruses In Human Cancer
dna tumor viruses in human cancer11
DNA Tumor Viruses In Human Cancer

Epidermodysplasia

verruciformis

Papilloma virus

dna tumor viruses in human cancer12

Papilloma Viruses

urogenital cancer

wart malignant squamous cell carcinoma

Papilloma viruses are found in 91% of women with cervical cancer

DNA Tumor Viruses In Human Cancer

Squamous cell carcinoma:

Larynx

Esophagus All histologically similar

Lung

10% of human cancers may be HPV-linked

dna tumor viruses in human cancer13
DNA Tumor Viruses In Human Cancer
  • Papilloma Viruses
  • 51 types identified - most common are types 6 and 11
  • most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers)

EPIDEMIOLOGIAL STUDIES BUT:

HPV 16 and HPV 18 do transform human keratinocytes

dna tumor viruses in human cancer14
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
  • PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
  • Polyoma virus transforms cells when the genome is incomplete
  • Early functions are necessary
dna tumor viruses in human cancer15
DNA Tumor Viruses In Human Cancer

Adenoviruses

Highly oncogenic in animals

Only part of virus integrated

Always the same part

Early functions

E1A region: 2 T antigens

E1B region: 1 T antigen

E1A and E1B = Oncogenes

dna tumor viruses in human cancer16
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

dna tumor viruses in human cancer17
DNA 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
dna tumor viruses in human cancer18

Hepatitis B Virus

DNA genome

RNA polymerase II

RNA Provirus

Reverse transcriptase

DNA genome

DNA Tumor Viruses In Human Cancer

Host enzyme

Viral enzyme

dna tumor viruses in human cancer hepatitis b continued
DNA Tumor Viruses In Human CancerHepatitis B continued
  • Vast public health problem
  • 10% of population in underdeveloped countries are chronic carriers
  • Long latency
dna tumor viruses in human cancer hepatitis b continued20
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

dna tumor viruses in human cancer21
DNA Tumor Viruses In Human Cancer

Summary

  • Can transform cells or have lytic life cycle
  • Often integrate into host genome
  • In transformation ONLY early genes are transcribed
rna tumor viruses

virus

virus

RNA 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

host

rna tumor viruses24
RNA Tumor Viruses

A normal retrovirus has:

3 genes

GAG : internal proteins

ENV: Envelope glycoproteins

POL: Enzymes

Reverse transcriptase

Integrase

Protease

rna tumor viruses25
RNA Tumor Viruses
  • RNA 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

rna tumor viruses27
RNA Tumor Viruses
  • Groups of Retroviruses
  • Oncovirinae
  • Tumor viruses and similar
  • Lentiviruses
  • Long latent period
  • Progressive chronic disease
  • Visna HIV
  • Spumavirinae

important

important

rna tumor viruses28
RNA Tumor Viruses

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
  • Human T cell lymphotropic virus -2 (HTLV-2)
  • Hairy cell leukemia
  • HIV?
rna tumor viruses29

Retrovirus Life Cycle

Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

RNA Tumor Viruses
rna tumor viruses30
RNA Tumor Viruses
  • Parental 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 DNA polymerase

Host splicing enzymes

Host RNA pol II

rna tumor viruses31
RNA Tumor Viruses

Drawback 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

Reverse transcriptase

Host RNA pol II

slide32

Problem of using RNA pol II to copy a gene

RNA synthesis initiation site

promotor

RNA pol II

RNA synthesis termination site

Viral genomicRNA

RT

primer

Reverse transcriptase

dsDNA

Result: New copy of viral RNA is shorter - lacks control sequences

rna tumor viruses33
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

BUT not copied!

rna tumor viruses34

Repeatregion

Repeatregion

DNA

U3 R U5 GAG POL ENV U3 R U5

LTR

RNA Tumor Viruses

Clue: Difference in the two forms

RNA

R U5 GAG POL ENV U3 R

slide35

promotor

POLII

RNA termination site

RNA initiation site

R U5

Viral RNA

U3 R

Reverse transcriptase

U3 R U5

U3 R U5

Long terminal repeats are formed

POLII

retroviruses can have only one promotor

POLII

RNA initiation site

RNA termination site

Retroviruses can have only one promotor

Contained in U3

LTR

LTR

POLII

Therefore only one long RNA can be made

Therefore mRNA requires processing

Explains why RNA has to be positive sense

U5

slide37

Rous Sarcoma Virus

R U5 GAG POL ENV U3 R

Some retroviruses have an extra gene

“typical retrovirus”

R U5 GAG POL ENV U3 R

SRC

slide38

Some retroviruses have an oncogene instead of their regular genes

Avian Myeloblastosis Virus

R U5 GAG POL MYB U3 R

Feline Sarcoma Virus (FSV)

R U5 dGAG FMS dENV U3 R

Avian Myelocytoma Virus (MC29)

R U5 dGAG MYC dENV U3 R

rna tumor viruses39
RNA Tumor Viruses

Viral Oncogene

V-onc

Cellular Proto-oncogene

C-onc

rna tumor viruses40
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
rna tumor viruses41
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

rna tumor viruses42

Avian Leukosis Virus (causes lymphomas)

R U5 GAG POL ENV U3 R

RNA Tumor Viruses

In contrast:

Chronically transforming retroviruses

cause tumors inefficiently after prolonged period of time

No oncogene! – How does it cause a tumor?

rna tumor viruses43
RNA Tumor Viruses

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)

  • Suggest tumor arose from one cell
  • Something must be important about this site for transformation
  • Crucial event must be rare
rna tumor viruses44
RNA Tumor Viruses

What is special about this site?

Myelocytoma tumors from several birds all have the oncogene close to this site

It is close to

C-myc!

Oncogenesis by promotor insertion

rna tumor viruses45
RNA Tumor Viruses

Could C-oncs be involved in NON-VIRAL cancers?

rna tumor viruses46

myb

mosmyc

fes

RNA Tumor Viruses

Genes can be assigned to sites on specific chromosomes

mos and myc : chromosome 8

fes: chromosome 15

cancers often result from gene translocations
Cancers often result from gene translocations

Burkitt’s Lymphoma

8:14 translocation

Break in chromosome 14 at q32

myc

Acute myelocytic leukemia7:159:1811:15:17

oncogenesis by rearrangement
Oncogenesis by rearrangement

Tumor c-onc new promotor

Burkitt’s lymphoma myc (8) Ig heavy (8 to 14)

Ig light (8 to 2)

T cell chronic lymphocytic myc T cell receptor (8 to 14)

leukemia

B-cell chronic lymphocytic bcl-1 Ig heavy (11 to 14)

leukemia bcl-2 Ig heavy (18 to 14)

T cell chronic lymphocytic tcl-1 T cell receptor

leukemia (14 inversion)

rna tumor viruses49
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

oncogenes
Oncogenes

Mutations in a proto-oncogene are dominant “gain of function” mutations

However other oncogenic genes show recessive mutations

  • Anti-Oncogenes
  • Loss of function mutations
  • Retinoblastoma
  • p53
proto oncogenes

Always binds

Always binds

Proto-oncogenes

Dominant mutations

Heterozygote

Homozygote

Allele 1 Allele 2 Allele 1 Allele 2

Normal Mutant Mutant Mutant

Binds under special circumstances

Mutant always binds

Mutant always binds

Mutant always binds

Function gained

Function gained

anti oncogenes

Mutation growth

Anti-Oncogenes

Recessive mutations

Rb Gene

Mutant Rb

Mutant Rb

Mutant Rb

Rb

Rb protein

Heterozygote

Homozygote

Function lost

Rb

Binds and controls cell cycle

No binding - Growth continues

anti oncogenes53
Anti-Oncogenes

Retinoblastoma gene has normal regulatory function in many cells

Involved in

Retinoblastoma

Lung carcinomas

Breast carcinomas

anti oncogenes54
Anti-Oncogenes
  • P53
  • Inactivated by
  • deletion
  • point mutation
  • In a series of colorectal cancers all showed:
  • Allele 1: partial or complete deletion
  • Allele 2: Point mutation
dna tumor viruses oncogenes
DNA Tumor VirusesOncogenes
  • Adenovirus E1A region 2
  • SV 40 Large T
  • Polyoma Large T
  • BK virus Large T
  • Lymphotropic virus Large T
  • Human papilloma Virus-16 E7
  • All have a sequence in common
  • Mutations in this region abolish transformation capacity
anti oncogenes56
Anti-Oncogenes

Retinoblastoma

Adenovirus E1A

Rb Gene

Rb protein

Rb

105kD

Rb

Rb

Cell cycle continues

Stops replication

anti oncogenes57
Anti-Oncogenes

p53

P53 gene

P53 gene

P53 gene

Papilloma

Hepatitis C

P53

P53

P53

Papilloma proteolysis

P53

DNA

Stops replication

replication

replication