Lec 16 - Oncogenic viruses

Question 1

List the features of transformation.

Answer 1

• Uncontrolled growth
• No contact inhibition = cells grow on top of each other
• No anchoring dependence
• Form colonies on semi-solid media
• Altered GF and nutrient requirements = don’t need as much

Question 2

What is carcinogenesis?

Answer 2

Complex multistage process by which cancer develops

Question 3

What is cancer?

Answer 3

• Group of diseases caused by abnormal cell growth
• Potential to metastasise = interferes with normal organ function

Question 4

What is a tumour?

Answer 4

Swelling from abnormal growth of tissue

Question 5

What is the difference between benign and malignant cancers?

Answer 5

Benign = restricted to 1 site
Malignant = uncontrolled growth with invasion and metastasis by blood and/or lymph

Question 6

Where does each of the following types of cancer originate from?
- Carcinoma
- Sarcoma
- Leukaemia
- Lymphoma and multiple myeloma
- CNS cancer

Answer 6

• Carcinoma = skin/epithelia
• Sarcoma = connective tissue
• Leukaemia = blood forming tissue ie bone marrow
• Lymphoma and multiple myeloma = immune cells
• CNS cancer = brain and spinal cord

Question 7

What is metastasis?

Answer 7

Secondary growth at a distance from primary cancer site

Question 8

What percentage of human cancers do viruses cause and what cancers?

Answer 8

20%
Liver and cervical cancers

Question 9

What cancers do the following viruses cause?
- Epstein Barr virus
- HBV
- Human T lymphotropic virus 1
- Human papillomavirus
- HCV
- Kaposi sarcoma associated herpesvirus
- Merkel cell polyomavirus

Answer 9

• Epstein Barr virus = Hodgkin and Burkitt lymphomas, carcinoma, sarcoma
• HBV = hepatocellular carcinoma
• Human T lymphotropic virus 1 = T cell leukaemia
• Human papillomavirus (HPV) = hepatocellular carcinoma, lymphoma, squamous cell carcinoma (cervical)
• HCV - hepatocellular carcinoma, lymphoma
• Kaposi sarcoma associated herpesvirus = Kaposi sarcoma, lymphoma
• Merkel cell polyomavirus = Merkel cell carcinoma (skin)

Question 10

What is the difference between RNA and DNA viruses in how they activate the cell cycle?

Answer 10

RNA viruses = encoded oncogenes to activate growth signalling pathways
DNA viruses = have tumour suppressor proteins to disrupt inhibitory pathways for proliferation

Question 11

What are proto-oncogenes and oncogenes?

Answer 11

• Proto-oncogenes = normal cellular proteins promoting regulation and proliferation of normal cells
• Oncogenes = mutated proto-oncogene allowing uncontrolled growth

Question 12

How do oncogenes and tumour suppressor genes induce abnormal cell growth? How many mutations are needed for each and what type of functional mutation is involved with each?

Answer 12

• Oncogenes = recessive (1 copy) gain of function stimulating proliferation
• Tumour suppressors = dominant (2 copies) loss of function allowing proliferation

Question 13

How do retroviruses convert proto-oncogenes to oncogenes?

Answer 13

Integration of viral genome

Question 14

What 2 processes do retroviruses use to induce transformation? Describe each.

Answer 14

1. Acutely transforming retrovirus = tumour in weeks; incorporates host genome into viral genome to make oncogenes then integrate oncogene into next cell
2. Slowly transforming retrovirus = tumour in months; integrates promoter into host genome’s proto-oncogene to convert it to oncogene

Question 15

What step in the HIV replication cycle - or any retrovirus replication cycle - causes transformation?

Answer 15

When viral integrase inserts cDNA into host genome

Question 16

What is Rous sarcoma virus (RSV) and how does it induce transformation?

Answer 16

• Chicken virus from altered Avian leukosis virus (ALV) by having polyprotein with src added to it
• src = tyrosine kinase which binds activated GF receptor and sends proliferation signal when phosphorylated
• Cellular c-src = C-terminal region to inhibit proliferation when phosphorylated
• Viral v-src = no C-terminal region = constitutive proliferation

Question 17

What are the 2 types of oncogene retroviruses?

Answer 17

1. Oncogene transducing retroviruses = oncogene in genome; causes transformation and rapid cancer
2. Oncogene deficient retroviruses = insert LTR to overexpress proto-oncogene; slow and minority cancer

Question 18

What cancers does Human T cell lymphotropic virus type 1 (HTLV-1) cause and how?

Answer 18

Adult cutaneous T cell lymphoma (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
Viral proteins unique to virus (no cell homologues)
1. Tax = activates host genes that promote proliferation and inhibit apoptosis; starts oncogenesis
2. HBZ = binds pRB to promote progression thru cell cycle; maintains oncogenesis

Question 19

How do DNA viruses contribute to oncogenesis? What cellular protein do they interact with?

Answer 19

Induce S phase for viral replication; interfere with tumour suppressor Rb protein

Question 20

How does HCV interact with Rb?

Answer 20

1. NS5B viral protein interacts with Rb in cytoplasm
2. Recruits E6AP E3 ubiquitin ligase to mark RB for degradation in proteosome

Question 21

What is the function of p53 and why do many viruses target it?

Answer 21

Tumour suppressor that arrests cell cycle after DNA damage then induces apoptosis if needed.
Virus infection causes DNA damage, so viruses alter p53 to avoid apoptosis.

Question 22

How does SV40, HPV and adenovirus target p53? Why do they have a similar effect despite different methods?

Answer 22

1. SV40 = large T antigen stabilises p53 in inactive state
2. HPV = E6 protein triggers degradation of p53
3. Adenovirus = E18 protein blocks transcription activation function of p53
   All have similar effect bc Rb’s binding site is matched to a degree by all 3 viruses