16 - Oncogenic Viruses

Question 1

Transformed cells

Answer 1

• Are immortal, grow indefinitely (e.g. Vero; HeLa)
• Loss of contact inhibition
• Loss of anchorage dependence
• Forms colonies in semi solid media
• Altered requirement for growth factors and nutrients
• Not necessarily oncogenic

Question 2

Carcinogenesis

Answer 2

Complex multistage process by which cancer develops

Question 3

Carcinoma

Answer 3

A malignancy that begins in skin or in tissues that line or cover internal organs

Question 4

Sarcoma

Answer 4

Begins in bone, cartilage, fat, muscle or other connective tissue

Question 5

% of human cancers that virla cancers account for

Answer 5

20%

Question 6

T/F: Malignancy is required for viral replication

Answer 6

FALSE

Question 7

T/F: Cancer is a side effect of host response or host-viral interaction

Answer 7

TRUE

Question 8

RNA tumour viruses and their oncogenes

Answer 8

Can activate cellular growth signalling pathways

Question 9

DNA tumour viruses and their tumour suppressor proteins

Answer 9

Can disrupt pathways that prevent cell proliferations

Question 10

Proto-oncogenes

Answer 10

Normal cellular proteins involved in promoting regulation and proliferation of normal cells

Question 11

Oncogenes

Answer 11

DNA sequence that has been altered via mutation from its original form (proto-oncogene), causing formation of cancerous tumour

Question 12

Oncogene single gain of function mutation

Answer 12

Single activating mutation enables oncogene to stimulate cell proliferation

Question 13

Tumour suppressor loss of function mutation

Answer 13

Two inactivating mutations eliminating the tumour suppressor gene, stimulating cell proliferation

Question 14

Retroviral insertion into proto-oncogenes

Answer 14

Can convert proto-oncogene (integral to control of cell division), into an oncogene

Question 15

Acutely transforming virus

Answer 15

• Produces tumours within weeks of infection
• Incorporates genetic material from a host cell into its own genome upon infection, forming a viral oncogene
• When the viral oncogene infects another cell vDNA which includes the oncogene is then integrated into the cellular genome

Question 16

Slowly transforming virus

Answer 16

• Requires months to elicit tumour growth
• Does not disrupt cellular function through the insertion of a viral oncogene
• Rather, it carries a promoter gene that is integrated into the cellular genome of the host cell next to or within a proto-oncogene, allowing conversion of the proto-oncogene to an oncogene

Question 17

Rous sarcoma virus

Answer 17

• Virus of chickens that contain oncogene viral(v)-src (an incorporated proto-oncogene cellular(c)-src)
• Altered form of avian leukosis virus that common infects chicken flocks

Question 18

Src

Answer 18

Tyrosine kinase that is involved in regulation of cell growth and differentiation

Question 19

c-Src

Answer 19

• Cytoplasmic signaling protein that can be phosphorylated at different sites.
• Responds to extracellular growth factors by binding to an activated growth factor receptor, becoming phosphorylated at certain positions, and subsequently sending a proliferation signal.

Question 20

c-Src C terminal regulatory region

Answer 20

Can also be phosphorylated, but in that case phosphorylation is inhibitory event that turns signalling off when extracellular stimulus is withdrawn

Question 21

RSV v-Src protein

Answer 21

Lacks C-terminal phosphorylation site so that v-Src is constitutively active, sending a constant proproliferation signal irrespective of the presence or absence of growth factors

Question 22

Two groups oncogenic retroviruses are classified into

Answer 22

• Oncogene transducing retrovirus
• Oncogene deficient retrovirus

Question 23

Oncogene transducing retrovirus

Answer 23

• Carry oncogene as part of their genome
• Rapidly leads to cancer in nearly 100% of susceptible animals

Question 24

Oncogene deficient retrovirus

Answer 24

• Cause cancer when insertion of the LTR causes overexpression of a cellular proto-oncogene
• Leads to cancer only some of the time, and does so slowly in infected animals;

Question 25

Human T cell lymphotropic virus type 1 (HTLV-1)

Answer 25

- Linked to adult cutaneous T-cell lymphoma and HTLV associated myelopathy - Oncogenic properties caused by two proteins (Tax and HBZ) encoded in the provirus - Neither protein has a known homolog among normal cellular genes.

Question 26

HTLV-1 Tax

Answer 26

- Transcription regulator - In addition to activating viral genes, also activates many host genes, including those that promote host cell proliferation and resistance to apoptosis.

Question 27

HBZ

Answer 27

- Can interact with pRB, therefore promoting cell cycling - Tax may be essential for starting the process of oncogenesis, but HBZ may be responsible for maintaining it - Active at different times over course of persistent oncogenic infections

Question 28

Rb

Answer 28

- Tumour suppressor gene that shuts off cell proliferation by binding to E2F (transcription factor) - If conditions are not right for cell division, cell cycle pauses at restriction point (no DNA synthesis) - R point is controlled by cellular protein Rb - Oncogenic DNA viruses (also HCV) put cells into S phase (so they can replicate DNA) by blocking Rb

Question 29

HCV NS5B protein

Answer 29

- Interacts with Rb in the cytoplasm and recruits the E3-ubiquitin ligase E6AP to facilitate ubiquitinylation of Rb - This targets Rb for degradation in proteasome

Question 30

Loss of Rb

Answer 30

Results in dysregulation of many Rb controlled process including comprised cell cycle checkpoints that guard against p53 dependent apoptosis

Question 31

How do viruses cause transformation

Answer 31

Via inactivation of tumour suppressor p53

Question 32

p53

Answer 32

- Arrests cell cycle in presence of damaged DNA and leads to apoptosis of cells whose DNA is irreversibly damaged - Virus infection causes DNA damage and hypoxia (activated p53) - MAny viruses alter p53 activity

Question 33

SV40 large T antigen

Answer 33

Stabilises p53 in inactive state

Question 34

HPV E6

Answer 34

Triggers degradation of p53

Question 35

Adeno E1B

Answer 35

Blocks transcriptional activation function of p53